Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula IV:  
                 
 
     wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R x  and R y  are independently selected from T-R 3 , or taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen; and R 2 , R 2 , T, and R 3  are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional PatentApplication 60/232,795 filed Sep. 15, 2000, US Provisional PatentApplication 60/257,887 filed Dec. 21, 2000 and US Provisional PatentApplication 60/286,949 filed Apr. 27, 2001, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicinal chemistry andrelates to compounds that are protein kinase inhibitors, compositionscontaining such compounds and methods of use. More particularly, thisinvention relates to compounds that are inhibitors of GSK-3 and Aurora-2protein kinases. The invention also relates to methods of treatingdiseases associated with these protein kinases, such as diabetes, cancerand Alzheimer's disease.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by better understanding of the structure of enzymes andother biomolecules associated with target diseases. One important classof enzymes that has been the subject of extensive study is the proteinkinases.

[0004] Protein kinases mediate intracellular signal transduction. Theydo this by effecting a phosphoryl extracellular and other stimuli causea variety of cellular responses to occur inside the cell. Examples ofsuch stimuli include environmental and chemical stress signals (e.g.osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin,H₂O₂), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor α(TNF-α )), and growth factors (e.g. granulocytemacrophage-colony-stimulating factor (GM-CSF), and fibroblast growthfactor (FGF). An extracellular stimulus may effect one or more cellularresponses related to cell growth, migration, differentiation, secretionof hormones, activation of transcription factors, muscle contraction,glucose metabolism, control of protein synthesis and regulation of cellcycle.

[0005] Many diseases are associated with abnormal cellular responsestriggered by protein kinase-mediated events. These diseases includeautoimmune diseases, inflammatory diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease or hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

[0006] Aurora-2 is a serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically,Aurora-2 may play a role in controlling the accurate segregation ofchromosomes during mitosis. Misregulation of the cell cycle can lead tocellular proliferation and other abnormalities. In human colon cancertissue, the aurora-2 protein has been found to be overexpressed. SeeBischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J.Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997,272, 13766-13771.

[0007] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim andKimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [wO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000)151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor elF2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

[0008] In a GSK-3 mediated pathway that is relevant for the treatment oftype II diabetes, insulin-induced signaling leads to cellular glucoseuptake and glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/386751. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

[0009] GSK-3 activity has also been associated with Alzheimer's disease.This disease is characterized by the well-known β-amyloid peptide andthe formation of intracellular neurofibrillary tangles. Theneurofibrillary tangles contain hyperphosphorylated Tau protein whereTau is phosphorylated on abnormal sites. GSK-3 has been shown tophosphorylate these abnormal sites in cell and animal models.Furthermore, inhibition of GSK-3 has been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)].Therefore, it is believed that GSK-3 activity may promote generation ofthe neurofibrillary tangles and the progression of Alzheimer's disease.

[0010] Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

[0011] As a result of the biological importance of GSK-3, there iscurrent interest in therapeutically effective GSK-3 inhbitors. Smallmolecules that inhibit GSK-3 have recently been reported [WO 99/65897(Chiron) and WO 00/38675 (SmithKline Beecham)].

[0012] For many of the aforementioned diseases associated with abnormalGSK-3 activity, other protein kinases have also been targeted fortreating the same diseases. However, the various protein kinases oftenact through different biological pathways. For example, certainquinazoline derivatives have been reported recently as inhibitors of p38kinase (WO 00/12497 to Scios). The compounds are reported to be usefulfor treating conditions characterized by enhanced p38-α activity and/orenhanced TGF-β activity. While p38 activity has been implicated in awide variety of diseases, including diabetes, p38 kinase is not reportedto be a constituent of an insulin signaling pathway that regulatesglycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38inhibition would not be expected to enhance glycogen synthesis and/orglucose uptake.

[0013] There is a continued need to find new therapeutic agents to treathuman diseases. The protein kinases aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant role in cancer, diabetes, Alzheimer's disease and otherdiseases.

DESCRIPTION OF THE INVENTION

[0014] It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of aurora-2 and GSK-3. Thesecompounds have the general formula I:

[0015] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0016] Z¹ Z⁴ are as described below;

[0017] Ring A is selected from the group consisting of:

[0018] G is Ring C or Ring D;

[0019] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0020] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0021] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0022] R^(x) and R^(y) are independently selected from T-R³ ₁, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T-R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0023] T is a valence bond or a C₁₋₄ alkylidene chain;

[0024] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0025] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂,13 N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂ ;

[0026] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0027] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(C₁₋₆aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the same nitrogen aretaken together to form a 5-8 membered heterocyclyl or heteroaryl ring;

[0028] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO2,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)2,—CON(R⁴)₂,—SO₂N(R⁴)2,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)_(2, 10)—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, orR⁵ and an adjacent substituent taken together with their interveningatoms form said ring fused to Ring C;

[0029] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, is —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N (R⁶)C(O)—, —C (R⁶)₂N (R⁶)C(O)O—, —C (R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N (R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0030] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C (R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0031] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0032] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0033] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0034] R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N (R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0035] As used herein, the following definitions shall apply unlessotherwise indicated. The phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted” or withthe term “(un) substituted.” Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and each substitution is independent of the other.

[0036] The term “aliphatic” as used herein means straight-chain,branched or cyclic C₁-C₁₂ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation but which are notaromatic. For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or(cycloalkyl) alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

[0037] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” meansalkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. The term “halogen” means F, Cl, Br, or I.

[0038] The term “heteroatom” means nitrogen, oxygen, or sulfur andincludes any oxidized form of nitrogen and sulfur, and the quaternizedform of any basic nitrogen. Also the term “nitrogen” includes asubstitutable nitrogen of a heterocyclic ring. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as inN-substituted pyrrolidinyl).

[0039] The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” as used herein means an aliphatic ring system having threeto fourteen members. The terms “carbocycle”, “carbocyclyl”,“carbocyclo”, or “carbocyclic” whether saturated or partiallyunsaturated, also refers to rings that are optionally substituted. Theterms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” alsoinclude aliphatic rings that are fused to one or more aromatic ornonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl,where the radical or point of attachment is on the aliphatic ring.

[0040] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

[0041] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein includes non-aromatic ring systems having five to fourteenmembers, preferably five to ten, in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

[0042] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromaticring groups having five to fourteen members. Examples of heteroarylrings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl,2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl,benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl,benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl,acridinyl, or benzoisoxazolyl. Also included within the scope of theterm “heteroaryl”, as it is used herein, is a group in which aheteroatomic ring is fused to one or more aromatic or nonaromatic ringswhere the radical or point of attachment is on the heteroaromatic ring.Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

[0043] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph),—CH₂(Ph), substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),(CH₂)yNHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is hydrogen, a substitutedor unsubstituted aliphatic group, an unsubstituted heteroaryl orheterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph), substituted—O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and V is a linkergroup. Examples of substituents on the aliphatic group or the phenylring of R° include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy; haloalkoxy, orhaloalkyl.

[0044] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Examples of suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring include those listed above for the unsaturated carbonof an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*,═NN(R*)₂, ═N—, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,where each R is independently selected from hydrogen, an unsubstitutedaliphatic group or a substituted aliphatic group. Examples ofsubstituents on the aliphatic group include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0045] Suitable substituents on the nitrogen of a non-aromaticheterocyclic ring include —R⁺, —N(R+)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an aliphatic group, a substitutedaliphatic group, phenyl (Ph), substituted Ph, —O(Ph), substituted—O(Ph), CH₂(Ph), substituted CH₂(Ph), or an unsubstituted heteroaryl orheterocyclic ring. Examples of substituents on the aliphatic group orthe phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

[0046] The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

[0047] The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

[0048] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

[0049] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³c— or ¹⁴C-enriched carbonare within the scope of this invention.

[0050] Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly GSK-3, in a biological sample or in a patient. Inanother embodiment, compounds of this invention and pharmaceuticalcompositions thereof, which comprise an amount of the protein kinaseinhibitor effective to treat or prevent a GSK-3-mediated condition and apharmaceutically acceptable carrier, adjuvant, or vehicle, may beformulated for administration to a patient.

[0051] The term “GSK-3-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition or state in which GSK-3is known to play a role. Such diseases or conditions include, withoutlimitation, diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia, and baldness.

[0052] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0053] Another aspect of the invention relates to inhibiting GSK-3activity in a biological sample, which method comprises contacting thebiological sample with a GSK-3 inhibitor of formula I.

[0054] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0055] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

[0056] The term “Aurora-2-mediated condition” or “disease”, as usedherein, means any disease or other deleterious condition in which Aurorais known to play a role. The term “Aurora-2-mediated condition” or“disease”, also means those diseases or conditions that are alleviatedby treatment with an Aurora-2 inhibitor. Such conditions include,without limitation, cancer. The term “cancer” includes, but is notlimited to the following cancers: colon and ovarian.

[0057] Another aspect of the invention relates to inhibiting Aurora-2activity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2 inhibitor of formula I, or acomposition thereof.

[0058] Another aspect of this invention relates to a method of treatingor preventing a CDK-2-mediated diseases with a CDK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0059] The term “CDK-2-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition in which CDK-2 is knownto play a role. The term “CDK-2-mediated condition” or “disease” alsomeans those diseases or conditions that are alleviated by treatment witha CDK-2 inhibitor. Such conditions include, without limitation, cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis. See Fischer, P. M. andLane, D. P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S.,Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs,9, 1849 (2000); Fry, D. W. and Garrett, M. D., Current Opinion inOncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000).

[0060] Another aspect of the invention relates to inhibiting CDK-2activity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0061] Another aspect of this invention relates to a method of treatingor preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0062] The term “ERK-mediated condition”, as used herein means anydisease state or other deleterious condition in which ERK is known toplay a role. The term “ERK-2-mediated condition” or “disease”, alsomeans those diseases or conditions that are alleviated by treatment witha ERK-2 inhibitor. Such conditions include, without limitation, cancer,stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia. ERK-2 protein kinase and itsimplication in various diseases has been described [Bokemeyer et al.1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651;Crews et al., 1992, Science 258, 478; Ejorbaek et al., 1995, J. Biol.Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al.,1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc.Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Freyand Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin.Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol.16, 589].

[0063] Another aspect of the invention relates to inhibiting ERK-2activity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0064] Another aspect of this invention relates to a method of treatingor preventing an AKT-mediated diseases with an AKT inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0065] The term “AKT-mediated condition”, as used herein, means anydisease state or other deleterious condition in which AKT is known toplay a role. The term “AKT-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with a AKTinhibitor. AKT-mediated diseases or conditions include, but are notlimited to, proliferative disorders, cancer, and neurodegenerativedisorders. The association of AKT, also known as protein kinase B, withvarious diseases has been described [Khwaja, A., Nature, pp. 33-34,1990; Zang, Q. Y., et al, Oncogene, 19 2000; Kazuhiko, N., et al, TheJournal of Neuroscience, 20 2000].

[0066] Another aspect of the invention relates to inhibiting AKTactivity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0067] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0068] The term “Src-mediated condition”, as used herein means anydisease state or other deleterious condition in which Src is known toplay a role. The term “Src-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with a Srcinhibitor. Such conditions include, without limitation, hypercalcemia,osteoporosis, osteoarthritis, cancer, symptomatic treatment of bonemetastasis, and Paget's disease. Src protein kinase and its implicationin various diseases has been described [Soriano, Cell, 69, 551 (1992);Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104,137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000);Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res.243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc.Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257(1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7,1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, CellGrowth Diff., 8, 269 (1997)].

[0069] Another aspect of the invention relates to inhibiting Srcactivity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0070] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

[0071] The term “patient” includes human and veterinary subjects.

[0072] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

[0073] The amount effective to inhibit protein kinase, for example,GSK-3 and Aurora-2, is one that measurably inhibits the kinase activitywhere compared to the activity of the enzyme in the absence of aninhibitor. Any method may be used to determine inhibition, such as, forexample, the Biological Testing Examples described below.

[0074] Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0075] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

[0076] Sterile injectable forms of the compositions of this inventionmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0077] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0078] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0079] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0080] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0081] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0082] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0083] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0084] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

[0085] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0086] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

[0087] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0088] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0089] The amount of the protein kinase inhibitor that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the patient treated and the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between 0.01-100 mg/kg body weight/day of the inhibitorcan be administered to a patient receiving these compositions.

[0090] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

[0091] Depending upon the particular protein kinase-mediated conditionto be treated or prevented, additional therapeutic agents, which arenormally administered to treat or prevent that condition, may beadministered together with the inhibitors of this invention. Forexample, in the treatment of diabetes other anti-diabetic agents may becombined with the GSK-3 inhibitors of this invention to treat diabetes.These agents include, without limitation, insulin or insulin analogues,in injectable or inhalation form, glitazones, alpha glucosidaseinhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

[0092] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation, chemotherapeuticagents or other anti-proliferative agents such as adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, and platinum derivatives; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

[0093] Those additional agents may be administered separately from theprotein kinase inhibitor-containing composition, as part of a multipledosage regimen. Alternatively, those agents may be part of a singledosage form, mixed together with the protein kinase inhibitor of thisinvention in a single composition.

[0094] Compounds of this invention may exist in alternative tautomericforms, as in tautomers 1 and 2 shown below. Unless otherwise indicated,the representation of either tautomer is meant to include the other.

[0095] R^(x) and R^(y) (at positions Z³ and Z⁴, respectively) may betaken together to form a fused ring, providing a bicyclic ring systemcontaining Ring A. Preferred RX/R^(y) rings include a 5-, 6-, 7-, or8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.Examples of Ring A systems are shown below by compounds I-A throughI-DD, wherein Z¹ is nitrogen or C(R⁹) and Z² is nitrogen or C(H).

[0096] Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D,I-E, I-F, I-G, I-H, I-I, I-J, I-K, I-L, and I-M, more preferably I-A,I-B, I-C, I-F, and I-H, and most preferably I-A, I-B, and I-H.

[0097] In the monocyclic Ring A system, preferred R^(x) groups, whenpresent, include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups, when present, include T-R³ wherein T isa valence bond or a methylene, and R³ is —R, —N(R⁴)₂, or —OR. Examplesof preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

[0098] In the bicyclic Ring A system, the ring formed when R^(x) andR^(y) are taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above. Preferred RX/R^(y)ring substituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,or —N(R⁴)₂ wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group.

[0099] R² and R^(2′) may be taken together to form a fused ring, thusproviding a bicyclic ring system containing a pyrazole ring. Preferredfused rings include benzo, pyrido, pyrimido, and a partially unsaturated6-membered carbocyclo ring, wherein said fused ring is optionallysubstituted. These are exemplified in the following formula I compoundshaving a pyrazole-containing bicyclic ring system:

[0100] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: -halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl,—NO₂, —O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl), —CN, —SO₂(C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl)is most preferably methyl.

[0101] When the pyrazole ring system is monocyclic, preferred R² groupsinclude hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un) substitutedphenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl) carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂O H, CH₂OCH₃,CH₂CH₂CH₂O H, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC (CH₃)₃, CONHCH (CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃,CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, andCO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0102] An embodiment that is particularly useful for treatingGSK3-mediated diseases relates to compounds of formula II:

[0103] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0104] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0105] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0106] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0107] T is a valence bond or a C₁₋₄ alkylidene chain; R² and R^(2′) areindependently selected from —R, —T—W—R⁶, or R² and R^(2′) are takentogether with their intervening atoms to form a fused, 5-8 membered,unsaturated or partially unsaturated, ring having 0-3 ring heteroatomsselected from nitrogen, oxygen, or sulfur, wherein each substitutablecarbon on said fused ring formed by R² and R^(2′) is substituted byhalo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and any substitutable nitrogen onsaid ring formed by R² and R^(2′) is substituted by R⁴;

[0108] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N (R⁷)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N (R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N (R⁷)₂;

[0109] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0110] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or twoR⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0111] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0112] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or C (R⁶)₂N (R⁶)CON(R⁶)—;

[0113] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0114] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0115] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and each R⁸ is independently selected from anoptionally substituted C₁₋₄ aliphatic group,13 OR⁶, —SR⁶, —COR⁶, —SO₂R⁶,—N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶.

[0116] When the R^(x) and R^(y) groups of formula II are taken togetherto form a fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-,or 8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula II are themono- and bicyclic systems shown below.

[0117] More preferred pyrimidine ring systems of formula II includeII-A, II-B, II-C, II-F, and I-H, most preferably II-A, II-B, and II-H.

[0118] In the monocyclic pyrimidine ring system of formula II, preferredR^(x) groups include hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups include T-R³ wherein T is a valence bondor a methylene, and R³ is —R, —N(R⁴)₂, or —OR. When R³ is —R or —OR, apreferred R is an optionally substituted group selected from C₁₋₆aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring.Examples of preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

[0119] In the bicyclic pyrimidine ring system of formula II, the ringformed when R^(x) and R^(y) are taken together may be substituted orunsubstituted. Suitable substituents include —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N (R⁴)CON (R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are asdefined above. Preferred R^(x)/R^(y) ring substituents include —halo,—R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is anoptionally substituted C₁₋₆ aliphatic group.

[0120] The R² and R^(2′) groups of formula II may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula II compounds having apyrazole-containing bicyclic ring system:

[0121] Preferred substituents on the R²/R^(2′) fused ring of formula IIinclude one or more of the following:

[0122] -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄alkyl), —CO₂ (C₁₋₄ alkyl), —CN, —SO₂ (C₁₋₄ alkyl), —SO₂NH₂, —OC(O)NH₂,—NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and —CO(C₁₋₄ alkyl),wherein the (C₁₋₄ alkyl)is a straight, branched, or cyclic alkyl group.Preferably, the (C₁₋₄ alkyl) group is methyl.

[0123] When the pyrazole ring system of formula II is monocyclic,preferred R² groups include hydrogen, a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include methyl, t-butyl, —CH₂OCH₃,cyclopropyl, furanyl, thienyl, and phenyl. A preferred R^(2′) group ishydrogen.

[0124] More preferred ring systems of formula II are the following,which may be substituted as described above, wherein R² and R^(2′) aretaken together with the pyrazole ring to form an indazole ring; andR^(x) and R^(y) are each methyl, or R^(x) and R^(y) are taken togetherwith the pyrimidine ring to form a quinazoline or tetrahydroquinazolinering:

[0125] Particularly preferred are those compounds of formula II-Aa,II-Ba, or II-Ha wherein ring C is a phenyl ring and R¹ is halo, methyl,or trifluoromethyl.

[0126] Preferred formula II Ring C groups are phenyl and pyridinyl. Whentwo adjacent substituents on Ring C are taken together to form a fusedring, Ring C is contained in a bicyclic ring system. Preferred fusedrings include a benzo or pyrido ring. Such rings preferably are fused atortho and meta positions of Ring C. Examples of preferred bicyclic RingC systems include naphthyl, quinolinyl and isoquinolinyl.

[0127] An important feature of the formula II compounds is the R¹ orthosubstituent on Ring C. An ortho position on Ring C or Ring D is definedrelative to the position where Ring A is attached. Preferred R¹ groupsinclude -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶. When R¹ is an optionally substituted C₁₋₆aliphatic group, the most preferred optional substituents are halogen.Examples of preferred R¹ groups include —CF₃, —Cl, —F, —CN, —COCH₃,—OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃, cyclohexyl, t-butyl,isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃, —SO₂NH₂, —N(CH₃)₂,—CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and —OCF₃.

[0128] On Ring C of formula II, preferred R⁵ substituents, when present,include -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and—N(R⁴)SO₂R. More preferred R⁵ substituents include —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0129] Preferred formula II compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0130] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring;

[0131] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 0-2 ring nitrogens;

[0132] (c) R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group,phenyl, —COR⁶ ₁, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂,—NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶; and

[0133] (d) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0134] More preferred compounds of formula II have one or more, and morepreferably all, of the features selected from the group consisting of:

[0135] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

[0136] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a 5-7 membered unsaturated or partially unsaturated carbocyclo ringoptionally substituted with —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0137] (c) R¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphaticgroup, phenyl, or —CN;

[0138] (d) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

[0139] (e) each R⁵ is independently selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0140] Even more preferred compounds of formula II have one or more, andmore preferably all, of the features selected from the group consistingof:

[0141] (a) Ring C is a phenyl ring optionally substituted by —R⁵;

[0142] (b) R^(x) is hydrogen or methyl and R^(y) is methyl,methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or anoptionally substituted group selected from 2-pyridyl, 4-pyridyl,piperidinyl, or phenyl, or R^(x) and R^(y) are taken together with theirintervening atoms to form an optionally substituted benzo ring orpartially unsaturated 6-membered carbocyclo ring;

[0143] (c) R¹ is -halo, a C₁₋₄ aliphatic group optionally substitutedwith halogen, or —CN;

[0144] (d) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂ (C₁-₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

[0145] (e) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic).

[0146] Representative compounds of formula II are shown below inTable 1. TABLE 1

[0147] In another embodiment, this invention provides a compositioncomprising a compound of formula II and a pharmaceutically acceptablecarrier.

[0148] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

[0149] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II.

[0150] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula II.This method is especially useful for diabetic patients.

[0151] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula II. This methodis especially useful in halting or slowing the progression ofAlzheimer's disease.

[0152] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula II. This method isespecially useful for treating schizophrenia.

[0153] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

[0154] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0155] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

[0156] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0157] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula II, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

[0158] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaII, as described above.

[0159] Another embodiment of this invention relates to compounds offormula III:

[0160] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0161] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0162] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, benzo ring or a 5-8 membered carbocyclo ring, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T-R³;

[0163] T is a valence bond or a C₁₋₄ alkylidene chain;

[0164] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0165] R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0166] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0167] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —So₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0168] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0169] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R6)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)₂N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C (R⁶)₂N (R⁶)CON(R⁶)—;

[0170] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C (R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0171] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0172] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0173] Preferred formula III Ring D monocyclic rings include substitutedand unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. When twoadjacent substituents on Ring D are taken together to form a fused ring,the Ring D system is bicyclic. Preferred formula III Ring D bicyclicrings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0174] Preferred R⁵ substituents on Ring D of formula III include halo,oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted or unsubstituted groupselected from 5-6 membered heterocyclyl, C₆-₁₀ aryl, or C₁₋₆ aliphatic.More preferred R⁵ substituents include -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆-₁₀ aryl, or C₁₋₆ aliphatic. Examples ofRing D substituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH,pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl,tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

[0175] Preferred rings formed when the R^(x) and R^(y) groups of formulaIII are taken together to form a fused ring include a 5-, 6-, or7-membered unsaturated or partially unsaturated carbocyclo ring, whereinany substitutable carbon on said fused ring is substituted by oxo orT-R³. Examples of preferred bicyclic ring systems are shown below.

[0176] Preferred substituents on the R^(x)/R^(y) fused ring of formulaIII include —R, oxo, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N (R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above. More preferredsubstituents on the R^(x)/R^(y) fused ring include halo, CN, oxo, C₁₋₆alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl) carbonyl, (C₁₋₆ alkyl) sulfonyl, mono-or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl. Examples of suchpreferred substituents include methoxy, methyl, isopropyl,methylsulfonyl, cyano, chloro, pyrrolyl, methoxy, ethoxy, ethylamino,acetyl, and acetamido.

[0177] Preferred R² substituents of formula III include hydrogen, C₁₋₄aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl,alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl) carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂O H, CH₂OCH₃, CH₂CH₂CH₂O H,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC (CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂O CH₃, CONHCH₂Ph,CONH(cyclohexyl), CON (Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃,CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, andCO(piperidin-1-yl).

[0178] When the R² and R^(2′) groups of formula III are taken togetherto form a ring, preferred R²/R^(2′) ring systems containing the pyrazolering include benzo, pyrido, pyrimido, 3-oxo-2H-pyridazino, and apartially unsaturated 6-membered carbocyclo ring. Examples of suchpreferred R²/R^(2′) ring systems containing the pyrazole ring includethe following:

[0179] Preferred substituents on the R²/R^(2′) fused ring of formula IIIinclude one or more of the following:

[0180] -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO2,—O(C₁₋₄alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(O)NH₂,—NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and —CO(C₁₋₄ alkyl),wherein the (C₁₋₄ alkyl)is a straight, branched, or cyclic alkyl group.Preferably, the (C₁₋₄ alkyl) group is methyl.

[0181] Preferred formula III compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0182] (a) Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0183] (b) R^(x) and R^(y) are taken together with their interveningatoms to form an optionally substituted benzo ring or a 5-7 memberedcarbocyclo ring; and

[0184] (c) R^(2′) is hydrogen or methyl and R² is T—W—R⁶ or R, wherein Wis —C(R⁶)₂O—, —C (R⁶)₂N (R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is anoptionally substituted group selected from C₁₋₆ aliphatic or phenyl, orR² and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstitutedbenzo, pyrido, pyrimido, or partiallyunsaturated 6-membered carbocyclo ring.

[0185] More preferred compounds of formula III have one or more, andmore preferably all, of the features selected from the group consistingof:

[0186] (a) Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0187] (b) R^(x) and R^(y) are taken together with their interveningatoms to form a benzo ring or a 5-7 membered carbocyclo ring optionallysubstituted with —R, oxo, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N (R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; and

[0188] (c)each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or c₁₋₆ aliphatic.

[0189] Even more preferred compounds of formula III have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0190] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a benzo or 6-membered partially unsaturated carbocycloring optionally substituted with halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy,(C₁₋₆alkyl) carbonyl, (C₁₋₆ alkyl) sulfonyl, mono- or dialkylamino,mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6membered heteroaryl;

[0191] (b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR,—OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selectedfrom 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

[0192] (c)R^(2′) is hydrogen and R² is selected from R² is hydrogen ormethyl and R² is T—W—R⁶ or R, wherein W is —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—,—CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)Co—, or —CON(R⁶)—, and R is anoptionally substituted group selected from C₁₋₆ aliphatic or phenyl, orR² and R^(2′) are taken together with their intervening atoms to form abenzo, pyrido, or partially unsaturated 6-membered carbocyclo ringoptionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl)is a straight,branched, or cyclic alkyl group.

[0193] Representative compounds of formula III are set forth in Table 2below. TABLE 2

[0194] In another embodiment, this invention provides a compositioncomprising a compound of formula III and a pharmaceutically acceptablecarrier.

[0195] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

[0196] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III.

[0197] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula III.This method is especially useful for diabetic patients.

[0198] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula III. Thismethod is especially useful in halting or slowing the progression ofAlzheimer's disease.

[0199] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula III. This method isespecially useful for treating schizophrenia.

[0200] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

[0201] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0202] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

[0203] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0204] One aspect of this invention relates to a method of inhibitingSrc activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

[0205] Another aspect relates to a method of treating a disease that isalleviated by treatment with a Src inhibitor, said method comprising thestep of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treatinghypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatictreatment of bone metastasis, and Paget's disease.

[0206] Another method relates to inhibiting GSK-3, Aurora, CDK-2, or Srcactivity in a biological sample, which method comprises contacting thebiological sample with the GSK-3, Aurora, CDK-2, or Src inhibitor offormula III, or a pharmaceutical composition thereof, in an amounteffective to inhibit GSK-3, Aurora, CDK-2, or Src.

[0207] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora, CDK-2, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIII, as described above.

[0208] Compounds of formula III, wherein R^(2′) is hydrogen and R^(x)and R^(y) are taken together with the pyrimidine ring to form anoptionally substituted quinazoline ring system, are also inhibitors ofERK-2 and AKT protein kinases.

[0209] Accordingly, another method of this invention relates to a methodof inhibiting ERK-2 or AKT activity in a patient, comprisingadministering to the patient a therapeutically effective amount of acomposition comprising a compound of formula III, wherein R² is hydrogenand R^(x) and R^(y) are taken together with the pyrimidine ring to forman optionally substituted quinazoline ring system.

[0210] Another aspect relates to a method of treating a disease that isalleviated by treatment with a ERK-2 or AKT inhibitor, said methodcomprising the step of administering to a patient in need of such atreatment a therapeutically effective amount of a composition comprisinga compound of formula III, wherein R^(2′) is hydrogen and R^(x) andR^(y) are taken together with the pyrimidine ring to form an optionallysubstituted quinazoline ring system. This method is especially usefulfor treating cancer, stroke, hepatomegaly, cardiovascular disease,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, restenosis, psoriasis, allergic disorders including asthma,inflammation, and neurological disorders.

[0211] Another embodiment of this invention relates to compounds offormula IV:

[0212] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0213] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0214] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring is optionally andindependently substituted by T—R³, and any substitutable nitrogen onsaid ring is substituted by R⁴;

[0215] T is a valence bond or a C₁₋₄ alkylidene chain;

[0216] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ringcontaining 0-3 ring heteroatoms selected from nitrogen, oxygen, orsulfur, wherein said fused ring is optionally substituted by up to threegroups independently selected from halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶;

[0217] R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0218] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0219] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, ortwo R⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0220] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N (R⁴)₂;

[0221] V is —O—, —S—, —SO—, —SO2—, —N(R⁶)SO₂—, —SO₂N (R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN (R⁶)—, —C (R⁶)═N—O—,—C(R⁶)₂N(R⁶)₂N(R⁶)—, —C (R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; Wis —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C (R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C (R⁶)═NN (R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C (R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

[0222] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0223] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclylring or heteroaryl.

[0224] Preferred formula IV Ring D monocyclic rings include substitutedand unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Preferredformula IV Ring D bicyclic rings include1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, and naphthyl. Examples of more preferred Ring D bicyclicrings include naphthyl and isoquinolinyl.

[0225] Preferred substituents on Ring D of formula IV include halo, oxo,CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—SR, —OR, —C(O)R, or substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. More preferredR⁵ substituents include -halo, —CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, ora substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples of Ring Dsubstituents include —OH, phenyl, methyl, CH₂O H, CH₂CH₂O H,pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl,tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

[0226] When the R^(x) and R^(y) groups of formula IV are taken togetherto form a fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-,or 8-membered unsaturated or partially unsaturated ring having 1-2heteroatoms. This provides a bicyclic ring system containing thepyrimidine ring. Examples of preferred pyrimidine ring systems offormula IV are the mono- and bicyclic systems shown below.

[0227] More preferred pyrimidine ring systems of formula IV includeIV-E, IV-G, IV-H, IV-J, IV-K, IV-L, IV-M, IV-T, and IV-U.

[0228] In the monocyclic pyrimidine ring system of formula IV, preferredR^(x) groups include hydrogen, amino, nitro, alkyl- or dialkylamino,acetamido, or a C₁₋₄ aliphatic group such as methyl, ethyl, cyclopropyl,isopropyl or t-butyl. Preferred R^(y) groups include T-R³ wherein T is avalence bond or a methylene, and R³ is —R, —N(R⁴)₂, or —OR. When R³ is—R or —OR, a preferred R is an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring. Examples of preferred R^(y) groups include 2-pyridyl,4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkyl- or dialkylamino, acetamido, optionally substituted phenyl such asphenyl, methoxyphenyl, trimethoxyphenyl, or halo-substituted phenyl, andmethoxymethyl.

[0229] In the bicyclic pyrimidine ring system of formula IV, the ringformed when R^(x) and R^(y) are taken together may be substituted orunsubstituted. Suitable substituents include —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N (R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)2,—N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are asdefined above for compounds of formula IV. Preferred R^(x)/R^(y) ringsubstituents include -halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or—N(R⁴)₂ wherein R is a substituted or unsubstituted C₁₋₆ aliphaticgroup.

[0230] The R² and R^(2′) groups of formula IV may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IV compounds having apyrazole-containing bicyclic ring system:

[0231] Preferred substituents on the R²/R^(2′) fused ring of formula IVinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁-₄ alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl)is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

[0232] When the pyrazole ring system of formula IV is monocyclic,preferred R² groups include hydrogen, a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include methyl, t-butyl, —CH₂OCH₃,cyclopropyl, furanyl, thienyl, and phenyl. A preferred R^(2′) group ishydrogen.

[0233] Preferred formula IV compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0234] (a) Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0235] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 1-2 ring heteroatoms; and

[0236] (c) R^(2′) is hydrogen or methyl and R² is T—W—R⁶ or R, wherein Wis —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C (R⁶)OC(O)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is anoptionally substituted group selected from C₁₋₆ aliphatic or phenyl, orR² and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido, or partiallyunsaturated 6-membered carbocyclo ring.

[0237] More preferred compounds of formula IV have one or more, and morepreferably all, of the features selected from the group consisting of:

[0238] (a) Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0239] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a 5-7 membered unsaturated or partially unsaturated ring having 1-2ring nitrogens, wherein said ring is optionally substituted with —R,halo, oxo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N (R⁴)CON (R⁴)₂, —N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂; and

[0240] (c) each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

[0241] Even more preferred compounds of formula IV have one or more, andmore preferably all, of the features selected from the group consistingof:

[0242] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a 6-membered unsaturated or partially unsaturated ringhaving 1-2 ring nitrogens, optionally substituted with halo, CN, oxo,C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl) carbonyl, (C₁₋₆ alkyl) sulfonyl,mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

[0243] (b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR,—OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selectedfrom 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

[0244] (c) R^(2′) is hydrogen and R² is T—W—R⁶ or R, wherein W is—C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, or—CON(R⁶)—, and R is an optionally substituted group selected from C₁₋₆aliphatic or phenyl, or R² and R^(2′) are taken together with theirintervening atoms to form a benzo, pyrido, or partially unsaturated6-membered carbocyclo ring optionally substituted with -halo, oxo,-N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄alkyl),—CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄alkyl), —NHC(O)(C₁₋₄ alkyl), —C (O)NH₂, or —CO(C₁₋₄ alkyl), wherein the(C₁₋₄ alkyl) is a straight, branched, or cyclic alkyl group.

[0245] Representative compounds of formula IV are set forth in Table 3below. TABLE 3

[0246] In another embodiment, this invention provides a compositioncomprising a compound of formula IV and a pharmaceutically acceptablecarrier.

[0247] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

[0248] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV.

[0249] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula IV.This method is especially useful for diabetic patients.

[0250] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula IV. This methodis especially useful in halting or slowing the progression ofAlzheimer's disease.

[0251] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula IV. This method isespecially useful for treating schizophrenia.

[0252] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

[0253] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0254] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

[0255] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0256] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula IV, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

[0257] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIV, as described above.

[0258] Another embodiment of this invention relates to compounds offormula V:

[0259] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0260] Z¹ is N, CR^(a), or CH and Z² is N or CH, provided that one of Z¹and Z² is nitrogen;

[0261] G is Ring C or Ring D;

[0262] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from −R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or 13 R⁸;

[0263] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0264] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0265] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T-R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0266] T is a valence bond or a C₁₋₄ alkylidene chain;

[0267] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0268] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC((═O)R, —N(R⁷)COR, —N(R⁷)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0269] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0270] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0271] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0272] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R”)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C (O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N (R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0273] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C (R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶))C(O)O—, —C(R⁶)═NN(R6)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R)—, —C (R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0274] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0275] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0276] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0277] R^(a) is selected from halo, —OR, —C((═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON (R⁴)₂, —SO₂N (R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁴)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms.

[0278] Compounds of formula V may be represented by specifying Z¹ and Z²as shown below:

[0279] When the R^(x) and R^(y) groups of formula V are taken togetherto form a fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-,or 8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyridine ring.Examples of preferred bicyclic ring systems of formula V are shownbelow.

[0280] More preferred bicyclic ring systems of formula V include Va-A,Vb-A, Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb-E, Vc-E, Va-J,Vb-J, Vc-J, Va-K, Vb-K, Vc-K, Va-L, Vb-L, Vc-L, Va-M, Vb-M, and Vc-M,most preferably Va-A, Vb-A, Vc-A, Va-B, Vb-B, and Vc-B.

[0281] In the monocyclic pyridine ring system of formula V, preferredR^(x) groups include hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups include T-R³ wherein T is a valence bondor a methylene, and R³ is —R, —N(R⁴)₂, or —OR. When R³ is —R or —OR, apreferred R is an optionally substituted group selected from C₁₋₆aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring.Examples of preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

[0282] In the bicyclic ring system of formula V, the ring formed whenR^(x) and R^(y) are taken together may be substituted or unsubstituted.Suitable substituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR,—NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N (R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is an optionally substitutedC₁₋₆ aliphatic group.

[0283] The R² and R^(2′) groups of formula V may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula V compounds having apyrazole-containing bicyclic ring system:

[0284] Preferred substituents on the R²/R^(2′) fused ring of formula Vinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0285] When the pyrazole ring system is monocyclic, preferred R² groupsinclude hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un) substitutedphenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl) carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂O H, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON (n-C₃H₇)2, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃,CO (morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂,and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0286] More preferred ring systems of formula V are the following, whichmay be substituted as described above, wherein R² and R^(2′) are takentogether with the pyrazole ring to form an optionally substitutedindazole ring; and R^(x) and R^(y) are each methyl, or R^(x) and R^(y)are taken together with the pyridine ring to form an optionallysubstituted quinoline, isoquinoline, tetrahydroquinoline ortetrahydroisoquinoline ring:

[0287] When G is Ring C, preferred formula V Ring C groups are phenyland pyridinyl. When two adjacent substituents on Ring C are takentogether to form a fused ring, Ring C is contained in a bicyclic ringsystem. Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred Ri groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶ ₁—OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡—C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

[0288] On Ring C preferred R⁵ substituents, when present, include -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. Morepreferred R⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵ substituents include—Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0289] When G is Ring D, preferred formula V Ring D monocyclic ringsinclude substituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula V Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0290] Preferred substituents on Ring D of formula V include one or moreof the following: halo, oxo, CN, —NO₂, —N (R⁴)₂, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

[0291] Preferred formula V compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0292] (a)Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0293] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T-R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 0-2 ring nitrogens; and

[0294] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2 ′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0295] More preferred compounds of formula V have one or more, and morepreferably all, of the features selected from the group consisting of:

[0296] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby −R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0297] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or a 5-7 membered partially unsaturated carbocycloring, said benzo or carbocyclo ring optionally substituted with —R,halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0298] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

[0299] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from -halo, —CN, —NO₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0300] Even more preferred compounds of formula V have one or more, andmore preferably all, of the features selected from the group consistingof:

[0301] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0302] (b) R^(x) is hydrogen or methyl and R^(y) is methyl,methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or anoptionally substituted group selected from 2-pyridyl, 4-pyridyl,piperidinyl, or phenyl, or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo ring or a 6-membered partiallyunsaturated carbocyclo ring optionally substituted with halo, CN, oxo,C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl,mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

[0303] (c) R² and R2′ are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,-C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂ (C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C14 alkyl), wherein the (C₁₋₄ alkyl)is a straight,branched, or cyclic alkyl group; and

[0304] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from —Cl, —F, —CN, —CF₃, —NH₂, —NH (C₁₋₄aliphatic), —N (CO₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic,and —CO₂(C₁₋₄ aliphatic).

[0305] Representative compounds of formula V are set forth in Table 4below. TABLE 4

[0306] In another embodiment, this invention provides a compositioncomprising a compound of formula V and a pharmaceutically acceptablecarrier.

[0307] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

[0308] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V.

[0309] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula V.This method is especially useful for diabetic patients.

[0310] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula V. This methodis especially useful in halting or slowing the progression ofAlzheimer's disease.

[0311] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula V. This method isespecially useful for treating schizophrenia.

[0312] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

[0313] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V. This method is especially useful for treating cancer, suchas colon, ovarian, and breast cancer.

[0314] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

[0315] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0316] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula V, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

[0317] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaV, as described above.

[0318] Another embodiment of this invention relates to compounds offormula VI:

[0319] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0320] G is Ring C or Ring D;

[0321] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from −R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0322] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0323] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0324] R^(y) is T—R^(3′);

[0325] T is a valence bond or a C₁₋₄ alkylidene chain;

[0326] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R² is substitutedby R⁴;

[0327] R³ is an optionally substituted group selected from C₁₋₆aliphatic, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

[0328] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0329] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0330] each R⁵ is independently selected from —R, halo, —OR, —C((═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N (R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC (═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0331] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N (R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C (R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

[0332] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C (R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N (R⁶)SO₂N (R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON (R⁶)—;

[0333] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a ⁵-6 memberedheterocyclyl or heteroaryl ring;

[0334] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0335] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶.

[0336] Preferred R^(y) groups of formula VI include T—R^(3′) wherein Tis a valence bond or a methylene, and R^(3′) is an optionallysubstituted group selected from C₁₋₆ aliphatic, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ringhaving 5-10 ring atoms. A preferred R^(3′) group is an optionallysubstituted group selected from C₃₋₆ carbocyclyl, phenyl, or a 5-6membered heteroaryl or heterocyclyl ring. Examples of preferred R^(y)include 2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl,cyclohexyl, and optionally substituted phenyl such as phenyl orhalo-substituted phenyl.

[0337] The R² and R^(2′) groups of formula VI may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula VI compounds having apyrazole-containing bicyclic ring system:

[0338] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄alkyl) group is methyl.

[0339] When the pyrazole ring system is monocyclic, preferred R² groupsof formula VI include hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl) arbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0340] When G is Ring C, preferred formula VI Ring C groups are phenyland pyridinyl. When two adjacent substituents on Ring C are takentogether to form a fused ring, Ring C is contained in a bicyclic ringsystem. Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R^(6,)—SO₂NH², —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

[0341] On Ring C preferred R⁵ substituents, when present, include —halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N (R⁴)SO₂R. Morepreferred R⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂ (C₁₋₄ aliphatic). Examples of such preferred R⁵ substituentsinclude —Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0342] When G is Ring D, preferred formula VI Ring D monocyclic ringsinclude substituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VI Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0343] Preferred substituents on formula VI Ring D include one or moreof the following: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

[0344] Preferred formula VI compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0345] (a) Ring C is selected from a phenyl or pyridinyl ring,optionally substituted by -R⁵, wherein when Ring C and two adjacentsubstituents thereon form a bicyclic ring system, the bicyclic ringsystem is selected from a naphthyl, quinolinyl or isoquinolinyl ring,and R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶; or Ring D is an optionally substituted ringselected from a phenyl, pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, azepanyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl ring;

[0346] (b) R^(y) is T-R^(3′) wherein T is a valence bond or a methylene;and

[0347] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0348] More preferred compounds of formula VI have one or more, and morepreferably all, of the features selected from the group consisting of:

[0349] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0350] (b) R^(y) is T—R^(3′), wherein T is a valence bond or a methyleneand R^(3′) is an optionally substituted group selected from C₁₋₆aliphatic, C₃₋₆ carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

[0351] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

[0352] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from -halo, —CN, —NO₂, -N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0353] Even more preferred compounds of formula VI have one or more, andmore preferably all, of the features selected from the group consistingof:

[0354] (a) R^(y) is T—R^(3′), wherein T is a valence bond or a methyleneand R^(3′), is an optionally substituted group selected from C₁₋₄aliphatic, C₃₋₆ carbocyclyl, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring;

[0355] (b) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0356] (c)R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO (C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

[0357] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic).

[0358] Another embodiment of this invention relates to compounds offormula VIa:

[0359] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0360] G is Ring C or Ring D;

[0361] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0362] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0363] R¹ is selected from —halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0364] T is a valence bond or a C₁₋₄ alkylidene chain; R² and R^(2′) aretaken together with their intervening atoms to form a fused, 5-8membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0365] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0366] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0367] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N (R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0368] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N (R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R )N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N (R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C (O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N (R⁶)CON(R⁶)—;

[0369] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N (R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0370] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0371] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0372] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶.

[0373] Preferred rings formed by the R² and R^(2′) groups of formula Viainclude benzo, pyrido, pyrimido, and a partially unsaturated 6-memberedcarbocyclo ring. These are exemplified in the following formula VIacompounds having a pyrazole-containing bicyclic ring system:

[0374] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—NO₂, —O(C₁₋₄ alkyl), —CO₂ (C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄alkyl), —NHC (O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

[0375] When G is Ring C, preferred formula VIa Ring C groups are phenyland pyridinyl. When two adjacent substituents on Ring C are takentogether to form a fused ring, Ring C is contained in a bicyclic ringsystem. Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R₆. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

[0376] On Ring C preferred R⁵ substituents, when present, include -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. Morepreferred R⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵ substituents include—Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0377] When G is Ring D, preferred formula VIa Ring D monocyclic ringsinclude substituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VIa Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0378] Preferred substituents on the formula Via Ring D include one ormore of the following: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂O H, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

[0379] Preferred formula VIa compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0380] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and

[0381] (b) R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0382] More preferred compounds of formula VIa have one or more, andmore preferably all, of the features selected from the group consistingof:

[0383] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0384] (b) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂ (C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl)is a straight,branched, or cyclic alkyl group; and

[0385] (c) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from -halo, —CN, —NO₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0386] Even more preferred compounds of formula VIa have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0387] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0388] (b) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, or partially unsaturated 6-membered carbocycloring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂ (C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

[0389] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, , —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic,and —CO₂(C₁₋₄ aliphatic).

[0390] Representative compounds of formula VI and IVa are set forth inTable 5 below. TABLE 5

[0391] In another embodiment, this invention provides a compositioncomprising a compound of formula VI or VIa and a pharmaceuticallyacceptable carrier.

[0392] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

[0393] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

[0394] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula VI orVIa. This method is especially useful for diabetic patients.

[0395] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VI or VIa. Thismethod is especially useful in halting or slowing the progression ofAlzheimer's disease.

[0396] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VI or VIa. This method isespecially useful for treating schizophrenia.

[0397] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

[0398] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa. This method is especially useful for treatingcancer, such as colon, ovarian, and breast cancer.

[0399] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

[0400] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa. This method is especially useful for treatingcancer, Alzheimer's disease, restenosis, angiogenesis,glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis,atherosclerosis, alopecia, and autoimmune diseases such as rheumatoidarthritis.

[0401] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula VI orVIa, or a pharmaceutical composition thereof, in an amount effective toinhibit GSK-3, Aurora or CDK-2.

[0402] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaVI or VIa, as described above.

[0403] Another embodiment of this invention relates to compounds offormula VII:

[0404] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0405] G is Ring C or Ring D;

[0406] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0407] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0408] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0409] R^(y) is hydrogen or T—R^(3″);

[0410] T is a valence bond, hydrogen, or a C₁₋₄ alkylidene chain;

[0411] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0412] R^(3″) is selected from an optionally substituted group selectedfrom C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0413] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0414] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or twoR⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0415] each R⁵ is independently selected from —R, halo, —OR, —C (═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N (R⁴)₂, —CON (R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0416] V is —O—, —S—, —SO—, —SO2—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N (R⁶)CON(R⁶)—, —N (R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C (R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N (R⁶)—, —C(R⁶)₂N (R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C (O)O—, —C (R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0417] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0418] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0419] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0420] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0421] R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N (R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0422] Preferred R^(y) groups of formula VII include T—R^(3″) wherein Tis a valence bond or a methylene. Preferred R^(3″) groups include anoptionally substituted group selected from C₃₋₆ carbocyclyl, phenyl, ora 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferredR^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl, and anoptionally substituted phenyl such as phenyl or halo-substituted phenyl.

[0423] The R² and R^(2′) groups of formula VII may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula VII compounds having apyrazole-containing bicyclic ring system:

[0424] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

[0425] When the pyrazole ring system of formula VII is monocyclic,preferred R² groups include hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl,(un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono-or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl) arbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂O H, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC (CH₃)₃, CONHCH (CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0426] When G is Ring C, preferred formula VII Ring C groups are phenyland pyridinyl. When two adjacent substituents on Ring C are takentogether to form a fused ring, Ring C is contained in a bicyclic ringsystem. Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO2NH2, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

[0427] On Ring C preferred R⁵ substituents, when present, include -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C16 aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. Morepreferred R⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵ substituents include—Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0428] When G is Ring D, preferred formula VII Ring D monocyclic ringsinclude substituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VII Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0429] Preferred substituents on Ring D include one or more of thefollowing: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH2OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

[0430] Preferred formula VII compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0431] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0432] (b) R^(y) is T—R^(3″), wherein T is a valence bond or amethylene; and

[0433] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0434] More preferred compounds of formula VII have one or more, andmore preferably all, of the features selected from the group consistingof:

[0435] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0436] (b) R^(y) is T—R^(3″), wherein T is a valence bond or a methyleneand R^(3″) is an optionally substituted group selected from C₃₋₆carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring;

[0437] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

[0438] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from -halo, —CN, —NO₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0439] Even more preferred compounds of formula VII have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0440] (a) R^(y) is T—R^(3″), wherein T is a valence bond or a methyleneand R^(3″) is an optionally substituted group selected from phenyl, or a5-6 membered heteroaryl or heterocyclyl ring;

[0441] (b) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0442] (c) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂ (C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

[0443] (d) Ring D is substituted by oxo or R⁵, wherein each R⁵ isindependently selected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, -O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic).

[0444] Representative compounds of formula VII are set forth in Table 6below. TABLE 6

[0445] In another embodiment, this invention provides a compositioncomprising a compound of formula VII and a pharmaceutically acceptablecarrier.

[0446] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

[0447] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII.

[0448] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula VII.This method is especially useful for diabetic patients.

[0449] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VII. Thismethod is especially useful in halting or slowing the progression ofAlzheimer's disease.

[0450] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VII. This method isespecially useful for treating schizophrenia.

[0451] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

[0452] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0453] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

[0454] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0455] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula VII, ora pharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

[0456] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaVII, as described above.

[0457] Another embodiment of this invention relates to compounds offormula VIII:

[0458] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0459] Z¹ is N or CR⁹, Z² is N or CH, and Z³ is N or CR^(x), providedthat one of Z¹ and Z³ is nitrogen;

[0460] G is Ring C or Ring D;

[0461] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from -R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0462] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by halo, oxo, or —R⁵, andat any substitutable ring nitrogen by —R⁴, provided that when Ring D isa six-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0463] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0464] R^(x) is T—R³;

[0465] T is a valence bond or a C₁₋₄ alkylidene chain;

[0466] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

[0467] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0468] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0469] each R⁴ is independently selected from —R⁷, —CoR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or twoR⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0470] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N (R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂;—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0471] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N (R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C (R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, _(—C(R) ⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C (R⁶)₂N (R⁶)SO₂N(R⁶)—, or —C (R⁶)₂N(R⁶)CON(R⁶)—;

[0472] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C (R⁶)₂N(R⁶)N(R⁶)—, C(R⁶)₂N(R⁶)SO₂N (R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0473] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0474] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0475] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0476] R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0477] Accordingly, the present invention relates to compounds offormula VIIIa, VIIIb, VIIIC and VIIId as shown below:

[0478] Preferred R^(x) groups of formula VIII include T—R³ wherein T isa valence bond or a methylene and R³ is CN, —R, or —OR. When R³ is —R,preferred R³ groups include an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring. When R³ is —OR, preferred R groups include anoptionally substituted group C₁₋₆ aliphatic group such as alkyl- ordialkylaminoalkyl and aminoalkyl. Examples of preferred R^(x) includeacetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl,imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl,isopropyl, t-butyl, NH₂CH₂CH₂NH, and NH₂CH₂CH₂O.

[0479] Preferred R⁹ groups of formula VIII, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁹ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O , (piperidin-1-yl)CH₂CH₂O ,and NH₂CH₂CH₂O .

[0480] The R² and R^(2′) groups of formula VIII may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula VIII compounds having apyrazole-containing bicyclic ring system:

[0481] Preferred substituents on the formula VIII R²/R^(2′) fused ringinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂ (C₁₋₄alkyl), —SO₂NH₂, —OC (O)NH₂, —NH₂SO₂ (C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C (O)NH₂, and —CO (C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl)is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl)group ismethyl.

[0482] When the pyrazole ring system of formula VIII is monocyclic,preferred R² groups include hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl,(un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono-or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl) carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂O H, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH3, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃,CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, andCO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0483] When G is Ring C, preferred formula VIII Ring C groups are phenyland pyridinyl. When two adjacent substituents on Ring C are takentogether to form a fused ring, Ring C is contained in a bicyclic ringsystem. Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

[0484] On Ring C preferred R⁵ substituents, when present, include -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. Morepreferred R⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and—CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵ substituents include—Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

[0485] When G is Ring D, preferred formula VIII Ring D monocyclic ringsinclude substituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VIII Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

[0486] Preferred R⁵ substituents on Ring D of formula VIII include halo,oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R; —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted or unsubstituted groupselected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.More preferred R⁵ substituents include -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples ofRing D substituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH,pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl,tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

[0487] Preferred formula VIII compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0488] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0489] (b)R^(x) is T—R³ wherein T is a valence bond or a methylene; and

[0490] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

[0491] More preferred compounds of formula VIII have one or more, andmore preferably all, of the features selected from the group consistingof:

[0492] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0493] (b) R^(x) is T—R³ wherein T is a valence bond or a methylene andR³ is CN, —R or —OR;

[0494] (c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

[0495] (d) each R⁵ is independently selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0496] Even more preferred compounds of formula VIII have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0497] (a) R^(x) is T—R³ wherein T is a valence bond or a methylene andR³ is —R or —OR wherein R is an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring;

[0498] (b) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0499] (c) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,-C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂ (C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁-₄ alkyl) is a straight,branched, or-cyclic alkyl group;

[0500] (d) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic); and

[0501] (e) R⁹ is R, OR, or N(R⁴)₂.

[0502] Representative compounds of formula VIII are set forth in Table 7below. TABLE 7

[0503] In another embodiment, this invention provides a compositioncomprising a compound of formula VIII and a pharmaceutically acceptablecarrier.

[0504] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

[0505] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII.

[0506] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula VIII.This method is especially useful for diabetic patients.

[0507] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VIII. Thismethod is especially useful in halting or slowing the progression ofAlzheimer's disease.

[0508] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VIII. This method isespecially useful for treating schizophrenia.

[0509] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

[0510] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0511] One aspect of this invention relates to a method of inhibitingCDK-2 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

[0512] Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0513] Another method relates to inhibiting GSK-3, Aurora, or CDK-2activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 or Aurora inhibitor of formula VIII, ora pharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

[0514] Each of the aforementioned methods directed to the inhibition ofGSK-3, Aurora or CDK-2, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaVIII, as described above.

[0515] The above formula I compounds contain a pyrazole ring bearing theR² and R^(2′) substituents. In their search for further inhibitors ofthe protein kinases GSK and Aurora, applicants sought to replace thepyrazole moiety of formula I with other heteroaromatic rings. One of themore effective pyrazole ring replacements was found to be a triazolering. Inhibitors having this triazole ring are otherwise structurallysimilar to the formula I compounds and are represented by the generalformula IX:

[0516] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0517] Z¹ is nitrogen or CR⁹ and Z² is nitrogen or CH, provided that atleast one of Z¹ and Z² is nitrogen;

[0518] G is Ring C or Ring D;

[0519] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0520] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0521] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0522] R^(x) and R^(y) are independently selected from T-R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0523] T is a valence bond or a C₁₋₄ alkylidene chain;

[0524] R² is —R or —T—W—R⁶;

[0525] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)2—OC (═O)R, —N(R⁷)COR, —N(R⁷)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N (R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0526] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0527] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or twoR⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0528] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N (R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0529] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶), —C(R)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0530] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C (R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0531] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0532] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0533] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0534] R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R₁, or —OC(═O)N(R⁴)₂.

[0535] Compounds of formula IX may exist in alternative tautomericforms, as in tautomers 1-3 shown below. Unless otherwise indicated, therepresentation of any of these tautomers is meant to include the othertwo.

[0536] The R^(x) and R^(y) groups of formula IX may be taken together toform a fused ring, providing a bicyclic ring system containing Ring A.Preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or 8-memberedunsaturated or partially unsaturated ring having 0-2 heteroatoms,wherein said R^(x)/R^(y) ring is optionally substituted. Examples ofRing A systems are shown below by compounds IX-A through IX-DD, whereinZ¹ is nitrogen or C(R⁹) and Z² is nitrogen or C(H).

[0537] Preferred bicyclic Ring A systems of formula IX include IX-A,IX-B, IX-C, IX-D, IX-E, IX-F, IX-G, IX-H, IX-I, IX-J, IX-K, IX-L, andIX-M, more preferably IX-A, IX-B, IX-C, IX-F, and IX-H, and mostpreferably IX-A, IX-B, and IX-H.

[0538] In the monocyclic Ring A system of formula IX, preferred R^(x)groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups, when present, include T—R³ wherein T isa valence bond or a methylene, and R³ is —R, —N(R⁴)₂, or —OR. Examplesof preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

[0539] In the bicyclic Ring A system of formula IX, the ring formed byR^(x) and R^(y) taken together may be substituted or unsubstituted.Suitable substituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR,—NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include -halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is an optionally substitutedC₁₋₆ aliphatic group.

[0540] Preferred R² groups of formula IX include hydrogen, C₁₋₄aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl,alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl) carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH (CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH2, and CO(piperidin-1-yl). A more preferred R² group for formula IXcompounds is hydrogen.

[0541] An embodiment that is particularly useful for treatingGSK3-mediated diseases relates to compounds of formula X wherein ring Ais a pyrimidine ring:

[0542] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0543] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0544] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0545] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0546] T is a valence bond or a C₁₋₄ alkylidene chain;

[0547] R² is —R or —T—W—R⁶;

[0548] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N (R⁷)COR, —N(R⁷)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N (R⁷)₂, —N (R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0549] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0550] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0551] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0552] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0553] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R ⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0554] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0555] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0556] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶.

[0557] Compounds of formula X are structurally similar to compounds offormula II except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y) and Ring C groups offormula X are as described above for the formula II compounds. Preferredformula X compounds have one or more, and more preferably all, of thefeatures selected from the group consisting of:

[0558] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring;

[0559] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 0-2 ring nitrogens;

[0560] (c) R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group,phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂,—NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶; and

[0561] (d) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.

[0562] More preferred compounds of formula X have one or more, and morepreferably all, of the features selected from the group consisting of:

[0563] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

[0564] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or a 5-7 membered carbocyclo ring, wherein said ringformed by R^(x) and R^(y) is optionally substituted with —R, halo, —OR,—C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —So₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)2,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0565] (c)R¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphaticgroup, phenyl, or —CN;

[0566] (d) R² is hydrogen or a substituted or unsubstituted groupselected from aryl or a C₁₋₆ aliphatic group; and

[0567] (e) each R⁵ is independently selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

[0568] Even more preferred compounds of formula X have one or more, andmore preferably all, of the features selected from the group consistingof:

[0569] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

[0570] (b) R^(x) is hydrogen or methyl and R^(y) is methyl,methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or anoptionally substituted group selected from 2-pyridyl, 4-pyridyl,piperidinyl, or phenyl, or R^(x) and R^(y) are taken together with theirintervening atoms to form an optionally substituted benzo ring or a6-membered carbocyclo ring;

[0571] (c) R¹ is -halo, a C₁₋₄ aliphatic group optionally substitutedwith halogen, or —CN;

[0572] (d) R² is hydrogen or a C₁₋₆ aliphatic group; and

[0573] (e) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂ (C₁₋₄ aliphatic).

[0574] Another embodiment of this invention relates to compounds offormula XI:

[0575] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0576] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, -R⁵ is hydrogen at each orthocarbon position of Ring D;

[0577] R^(x) and R^(y) are taken together with their intervening atomsto form a fused benzo ring or 5-8 membered carbocyclo ring, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³;

[0578] T is a valence bond or a C₁₋₄ alkylidene chain;

[0579] R² is —R or —T—W—R⁶;

[0580] R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0581] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0582] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or twoR⁴ on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0583] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0584] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0585] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)═NN(R⁶)—,—C (R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R^(—))—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0586] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0587] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0588] Compounds of formula XI are structurally similar to compounds offormula III except for the replacement of the pyrazole ring moiety bythe triazole ring moiety. Preferred R², R^(x), R^(y) , and Ring D groupsof formula XI are as described above for the formula III compounds.Preferred formula XI compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

[0589] (a) Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0590] (b) R^(x) and R^(y) are taken together with their interveningatoms to form an optionally substituted benzo ring or 5-7 memberedcarbocyclo ring; and

[0591] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.

[0592] More preferred compounds of formula XI have one or more, and morepreferably all, of the features selected from the group consisting of:

[0593] (a) Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0594] (b) R^(x) and R^(y) are taken together with their interveningatoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein saidring formed by R^(x) and R^(y) is optionally substituted with —R, oxo,halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N (R⁴)COR, —N (R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0595] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl or a C₁₋₆ aliphatic group; and

[0596] (d) each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

[0597] Even more preferred compounds of formula XI have one or more, andmore preferably all, of the features selected from the group consistingof:

[0598] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a benzo ring or 6-membered carbocyclo ring, wherein saidring formed by R^(x) and R^(y) is optionally substituted with halo, CN,oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl) carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

[0599] (b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR,—OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selectedfrom 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

[0600] (c) R² is hydrogen or a C₁₋₆ aliphatic group.

[0601] Another embodiment of this invention relates to compounds offormula XII:

[0602] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0603] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0604] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring is optionally andindependently substituted by T-R³, and any substitutable nitrogen onsaid ring is substituted by R⁴;

[0605] T is a valence bond or a C₁₋₄ alkylidene chain;

[0606] R² is —R or —T—W—R⁶;

[0607] R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂;—N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0608] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0609] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0610] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0611] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0612] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C (R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

[0613] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0614] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclylring or heteroaryl.

[0615] Compounds of formula XII are structurally similar to compounds offormula IV except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y) , and Ring D groups offormula XII are as described above for the formula IV compounds.Preferred formula XII compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

[0616] (a) Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0617] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 1-2 ring heteroatoms; and

[0618] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.

[0619] More preferred compounds of formula XII have one or more, andmore preferably all, of the features selected from the group consistingof:

[0620] (a) Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0621] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a 5-7 membered unsaturated or partially unsaturated ring having 1-2ring nitrogens, wherein said ring is optionally substituted with —R,halo, oxo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC (═O)N(R⁴)₂;

[0622] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl or a C₁₋₆ aliphatic group; and

[0623] (d) each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N (R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

[0624] Even more preferred compounds of formula XII have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0625] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a 6-membered unsaturated or partially unsaturated ringhaving 1-2 ring nitrogens, optionally substituted with halo, CN, oxo,C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl,mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

[0626] (b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR,—OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selectedfrom 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

[0627] (c) R² is hydrogen or a C₁₋₆ aliphatic group.

[0628] Another embodiment of this invention relates to compounds offormula XIII:

[0629] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0630] Z¹ is nitrogen, CR^(a), or CH, and Z² is nitrogen or CH; providedthat one of Z¹ and Z² is nitrogen;

[0631] G is Ring C or Ring D;

[0632] Ring C is selected from a phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C hasone or two ortho substituents independently selected from —R¹, anysubstitutable non-ortho carbon position on Ring C is independentlysubstituted by —R⁵, and two adjacent substituents on Ring C areoptionally taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, said fused ringbeing optionally substituted by halo, oxo, or —R⁸;

[0633] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D issubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D;

[0634] R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings eachoptionally substituted by up to three groups independently selected fromhalo, oxo, or —R⁸ said C₁₋₆ aliphatic group optionally substituted withhalo, cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

[0635] R^(x) and R^(y) are independently selected from T—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-8 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereinany substitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

[0636] T is a valence bond or a C₁₋₄ alkylidene chain;

[0637] R² is —R or —T—W—R⁶;

[0638] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂ ;

[0639] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0640] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring;

[0641] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacentsubstituent taken together with their intervening atoms form said ringfused to Ring C;

[0642] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON (R⁶)—, —N(R⁶)SO₂N(R)—,—N(R⁶)N (R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C (R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(═NN(R⁶)—, —C(R⁶)═N—O—, —C (R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0643] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N (R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0644] each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0645] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

[0646] each R⁸ is independently selected from an optionally substitutedC₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂,—CN, —NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

[0647] R^(a) is selected from halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁴)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms.

[0648] Compounds of formula XIII may be represented by specifying Z¹ andZ² as shown below:

[0649] Compounds of formula XIII are structurally similar to compoundsof formula V except for the replacement of the pyrazole ring moiety bythe triazole ring moiety. Preferred R², R^(x), R^(y), R^(a), and Ring Ggroups of formula XIII are as described above for the formula Vcompounds. Preferred formula XIII compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0650] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2, 3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

[0651] (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, orR^(x) and R^(y) are taken together with their intervening atoms to forman optionally substituted 5-7 membered unsaturated or partiallyunsaturated ring having 0-2 ring nitrogens; and

[0652] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.

[0653] More preferred compounds of formula XIII have one or more, andmore preferably all, of the features selected from the group consistingof:

[0654] (a) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

[0655] (b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR,or R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or a 5-7 membered carbocyclo ring, wherein said ringformed by R^(x) and R^(y) is optionally substituted with —R, halo, —OR,—C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)So₂R, or —OC(═O)N(R⁴)₂;

[0656] (C) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, or a C₁₋₆ aliphatic group; and

[0657] (d) each R⁵ is independently selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R, and, when Ring Gis Ring D, Ring D is substituted by oxo or R⁵.

[0658] Even more preferred compounds of formula XIII have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0659] (a) R^(x) is hydrogen or methyl and R^(y) is methyl,methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or anoptionally substituted group selected from 2-pyridyl, 4-pyridyl,piperidinyl, or phenyl, or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo ring or a 6-membered carbocyclo ringwherein said ring formed by R^(x) and R^(y) is optionally substitutedwith halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl,mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

[0660] (b) Ring C is a phenyl or pyridinyl ring, optionally substitutedby —R⁵, wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

[0661] (c) R² is hydrogen or a C₁₋₆ aliphatic group; and

[0662] (d) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic), and when Ring G is Ring D, Ring Dis substituted by oxo or R⁵.

[0663] Representative compounds of formula IX are shown below in Table8. TABLE 8

[0664] In another embodiment, this invention provides a compositioncomprising a compound of formula IX and a pharmaceutically acceptablecarrier.

[0665] One aspect of this invention relates to a method of inhibitingGSK-3 activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IX.

[0666] Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IX.

[0667] Another aspect relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula IX.This method is especially useful for diabetic patients.

[0668] Another aspect relates to a method of inhibiting the productionof hyperphosphorylated Tau protein in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula IX. This methodis especially useful in halting or slowing the progression ofAlzheimer's disease.

[0669] Another aspect relates to a method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula IX. This method isespecially useful for treating schizophrenia.

[0670] One aspect of this invention relates to a method of inhibitingAurora activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IX.

[0671] Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IX. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

[0672] Another method relates to inhibiting GSK-3 or Aurora activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula IX, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3 or Aurora.

[0673] Each of the aforementioned compositions and methods directed tothe inhibition of GSK-3 or Aurora, or the treatment of a diseasealleviated thereby, is preferably carried out with a preferred compoundof formula IX, as described above.

[0674] The compounds of this invention may be prepared as illustrated bythe Synthetic Methods below, by the Synthetic Examples described hereinand by general methods known to those skilled in the art.

[0675] General Synthetic Methods

[0676] The general synthetic methods below provide a series of generalreaction routes that were used to prepare compounds of this invention.Methods A-F below are particularly useful for preparing formula IIcompounds. In most cases, Ring C is drawn as a phenyl ring bearing anortho R¹ substituent. However, it will be apparent to one skilled in theart that compounds having other Ring C groups may be obtained in asimilar manner. Methods analogous to methods A-F are also useful forpreparing other compounds of this invention. Methods F-I below areparticulary useful for preparing compounds of formula III or IV.

[0677] Method A is a general route for the preparation of compoundswherein ring C is an aryl or heteroaryl ring. Preparation of thestarting dichloropyrimidine 1 may be achieved in a manner similar tothat described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. Thechlorine in position 4 of intermediate 1 may be replaced by anaminopyrazole or aminoindazole to provide intermediate 2 in a mannersimilar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring Cis then introduced using a boronic ester under palladium catalysis (seeTetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by thefollowing procedure.

[0678] A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) inPOCl₃ (60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) isheated under reflux for 2 h. Excess POCl₃ is evaporated under vacuum,the residue is poured into ice, and the precipitate is collected byfiltration. The crude solid 2,4-dichloroquinazoline product may be usedwithout further purification.

[0679] To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) inanhydrous ethanol (150 mL) is added S-methyl-1H-pyrazol-3-yl amine (3.2g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, andthe resulting precipitate is collected by filtration, washed withethanol, and dried under vacuum to afford(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine.

[0680] To a solution of(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19mmol) in DMF (1.0 mL) is added the desired arylboronic acid (0.38 mmol),2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Undernitrogen, PdCl2(dppf)(0.011 mmol) is added in one portion. The reactionmixture is then heated at 80° C. for 5 to 10 hours, cooled to roomtemperature, and poured into water (2 mL). The resulting precipitate iscollected by filtration, washed with water, and purified by HPLC.

[0681] Methods B through F describe routes where the pyrazole ringsystem is introduced after Ring C and the pyrimidine ring portion arefirst constructed. A versatile intermediate is the 4-chloropyrimidine 4,which is readily obtained from pyrimidinone 3 as shown in Method B(i).This reaction sequence is generally applicable for a variety of Ring Cgroups including aliphatic, aryl, heteroaryl, or heterocyclyl. See J.Med. Chem., 38, 3547-3557 (1995).

[0682] For quinazoline ring systems (where R^(x) and R^(y) are takentogether to form a benzo ring), the useful intermediate 6 may beobtained by condensing an anthranilic acid or its derivative with abenzamidine as shown in Method B(ii) or by condensing a benzoylchloridewith an anthranilamide as shown in Method B(iii). Many substitutedanthranilic acid, anthranilamide, benzamidine and benzoylchloridestarting materials may be obtained by known methods. See Aust. J. Chem.,38, 467-474 and J. Med. Chem., 38, 3547-3557 (1995). Method B(iii) isillustrated by the following procedure.

[0683] To a solution of anthranilamide (33 mmol) in THF and CH₂Cl₂ (1:1,70 mL) is added the desired benzoylchloride (33 mmol), and triethylamine(99 mmol) at room temperature. The mixture is stirred for about 14hours. The resulting precipitate is collected by filtration, washed withCH₂Cl₂ and water, and dried under vacuum. The crude2-benzoylaminobenzamide may be used directly for the next step withoutfurther purification.

[0684] To a solution of the above crude product (13 mmol) in ethanol (50mL) is added NaOEt (26 mmol) at room temperature. The mixture is heatedunder reflux for 48 to 96 h. The solvent is evaporated and the residueis neutralized using concentrated HCl to pH 7. The product is thencollected by filtration and dried under vacuum to provide2-phenyl-3H-quinazolin-4-one that may be used without furtherpurification.

[0685] To a suspension of the above product (12 mmol) in POCl₃ (120mmol) is added tri-n-propylamine (24 mmol). The mixture is heated underreflux for 1h. After removal of the excess POCl₃ by evaporation, theresidue is dissolved in ethyl acetate, and washed with 1N NaOH (twice)and water (twice). The organic layer is dried over MgSO₄, the solvent isevaporated under vacuum, and the crude product is purified by flashchromatography (eluting with 10% of ethyl actetate in hexanes) to give4-chloro-2-aryl quinazoline.

[0686] To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF(or THF, ethanol)(1 mL) is added the desired aminopyrazole oraminoindazole (0.32 mmol). The mixture is heated in DMF (or THF underreflux) at 100 to 110° C. for 16 h (or in ethanol at 130-160° C. for 16hours) and then poured into water (2 mL). The precipitate is collectedby filtration and purified by HPLC.

[0687] Methods C and D(i) above employ β-ketoesters 8 and 10,respectively, as pyrimidinone precursors. The substitution pattern ofthe R^(x) and R^(y) groups on the pyrimidinone ring will be reversed ifa chlorocrotonate 11 (Synth. Comm, (1986), 997-1002), instead of thecorresponding β-ketoester 10, is condensed with the desired benzamidine.These methods are illustrated by the following general procedure.

[0688] To a solution of a β-ketoester (5.2 mmol) and amidinium chloride(5.7 mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). Themixture is heated under reflux for 7-14 hours. After evaporation theresulting residue is dissolved in water, acidified with concentrated HClto pH 6, and then filtered to obtain a solid product2-aryl-3H-pyrimidin-4-one (yield 75-87%), which may be purified by flashcolumn chromatography if needed. To this pyrimidinone (3.7 mmol) isadded POCl₃ (4 mL) and n-Pr₃N (1.4 mL). The mixture is heated underreflux for 1 hour. After evaporation of the excess POCl₃, the residue isdissolved in ethyl acetate, washed with 1N NaOH solution (three times)and NaHCO₃ (once), and dried over MgSO₄. The solvent is removed undervacuum and the residue is purified by flash column chromatographyeluting with 10% of ethyl acetate in hexanes to give2-aryl-4-chloro-pyrimidine as a pale yellow syrup. This crude productmay be treated with a 3-aminopyrazole or 3-aminoindazole as describedabove.

[0689] Method D(ii) above shows a general route for the preparation ofthe present compounds, such as compound 40, wherein R^(y) is N(R⁴)₂. SeeIl Farmaco, 52 (1) 61-65 (1997). Displacement of the 6-chloro group isexemplified here using morpholine. This method is illustrated by thefollowing procedure.

[0690] To a solution of 2-methylmalonic acid diethyl ester (5 mmol) andsodium ethoxide (15 mmol) is added the appropriate amidine salt (5 mmol)in ethanol (10 mL) and the reaction heated at reflux for 2-24 hours. Theresidue is dissolved in water and acidified with 2N HCl. The resultingprecipitate is filtered off and further purified by flash chromatography(yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) isadded POCl₃ (32 mmol) and tri-n-propylamine (6.4 mmol) and the reactionrefluxed is for 1h. After evaporation of excess POCl₃, the residue isdissolved in ethyl acetate, basified with 1N NaOH, separated and theaqueous phase twice more extracted with ethyl acetate. The combinedorganics are dried (sodium sulfate) and evaporated. Purification byflash chromatography provides the dichloropyrimidine (38) as a yellowoil in 23% yield.

[0691] A solution of 38 (0.33 mmol) in methanol (5 mL) is treated withan amine, exemplified here using morpholine (0.64 mmol) and refluxed 1hour. After evaporation of solvent, the residue is purified by flashchromatography to provide the mono-chloropyrimidine 39 as a colorlessoil in 75% yield.

[0692] The mono-chloropyrimidine, 39, (0.19 mmol) may be treated with a3-aminopyrazole or 3-aminoindazole compound in a manner substantiallysimilar those described above in Methods A and B.

[0693] As shown by Method E, an acyl isocyanate 12 may be condensed withan enamine to provide pyrimidinone 9 (J. Org. Chem (1993), 58, 414-418;J.Med.Chem., (1992), 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214).This method is illustrated by the following general procedure.

[0694] The enamine is prepared according to W. White, et al, J. OrgChem. (1967), 32, 213-214. The acyl isocyanate is prepared according toG Bradley, et al, J Med. Chem. (1992), 35, 1515-1520. The couplingreaction then follows the procedure of S Kawamura, et al, J. Org. Chem,(1993), 58, 414-418. To the enamine (10 mmol) in tetrahydrofuran (30 mL)at 0° C. under nitrogen is added dropwise over 5 min a solution of acylisocyanate (10 mmol) in tetrahydrofuran (5 mL). After stirring for 0.5h, acetic acid (30 mL) is added, followed by ammonium acetate (50 mmol).The mixture is refluxed for 2 h with continuous removal oftetrahydrofuran. The reaction is cooled to room temperature and ispoured into water (100 mL). The precipitate is filtered, washed withwater and ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

[0695] Method F shows a general route for the preparation of the presentcompounds wherein R^(x) and R^(y) are taken together to form a 5-8membered partially unsaturated saturated or unsaturated ring having 1-3heteroatoms. The condensation of a 2-amino-carboxylic acid, such as2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone14. Treatment of 14 with ammonium hydroxide will furnish the benzamide15 which may be cyclized to a2-(substituted)-pyrido[2,3-d][1,3]pyrimidin-4-one 16. This method isillustrated by the following procedure.

[0696] 2-(Trifluoromethyl) benzoyl chloride (4.2 ml, 29.2 mmol) is addeddropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in20 ml of pyridine. The reaction mixture is heated at 158° C. for 30 minthen cooled to room temperature. The reaction is poured into 200 ml ofwater and an oil forms which solidifies upon stirring. The solid iscollected by vacuum filtration and washed with water and diethyl ether.The product is dried to give2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60%yield) which may be used in the next step without further purification.

[0697] 2-(2-Trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.51g) is stirred in 30% ammonium hydroxide (25 ml) at room temperatureovernight. The resulting precipitate is filtered and rinsed with waterand diethyl ether. The precipitate is dried under vacuum at 50 C.overnight to give 2-(2-trifluoromethyl-benzoylamino)-nicotinamide (850mg, 33% yield)

[0698] 2-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800mg, 2.6 mmol)is dissolved in 10 ml of ethanol. Potassium ethoxide (435 mg, 5.2 mmol)is added to the solution which is heated to reflux for 16 h. Thereaction mixture is evaporated in vacuo to afford a gummy residue thatis dissolved in water and acidified with 10% sodium hydrogen sulfate topH 7. The resulting precipitate is filtered and dried under vacuum at 50C. to give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3-d]pyrimidin-4-one.

[0699] Method G

[0700] Method G is analogous to Method B(i) above. This method isillustrated by the following general procedure.

[0701] 2-(3,4-Dichloro-phenyl)-3H-quinazolin-4-one (1 g, 3.43 mmol) issuspended in phosphorus oxychloride (4 mL) and the reaction mixture wasstirred at 110° C. for 3 hours. The solvents are then evaporated and theresidue is treated carefully with an ice cold aqueous saturated solutionof NaHCO₃. The solid is collected by filtration and washed with ether togive 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline as a white solid (993mg, 93%).

[0702] To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400mg, 1.29mmol) in THF (30 mL) is added 3-amino-5mehtyl pyrazole (396 mg, 2.58mmol) and the reaction mixture is heated at 65° C. overnight. Thesolvents are then evaporated and the residue triturated with ethylacetate, filtered and washed with a minimum amount of ethanol to give[2-(3,4-dichlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amineas a white solid (311 mg 65%): mp 274° C.; 1H NMR (DMSO) δ 2.34 (3H, s),6.69 (1H, s), 7.60 (1H, m), 7.84 (1H, d), 7.96 (2H, d), 8.39 (1H, dd),8.60 (1H, d), 8.65 (1H, d), 10.51 (1H, s), 12.30 (1H, s); IR(solid)1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS370.5 (M+H)⁺.

[0703] The THF solvent used in the previous step may be replaced byother organic solvents such as ethanol, N,N-dimethylformamide, ordioxane.

[0704] Method H shows routes in which a Ring D aryl group bearing ahalogen (X is Br or I) may be converted to other formula III compounds.Method H(i) shows a phenylboronic acid coupling to Ring D to providecompound 18 and Method H(ii) shows an acetylene coupling to providecompound 19. Substituent X in compound 17 may be bromine or iodine.These methods are illustrated by the following procedures.

[0705] Method H(i). To a mixture of [2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (196 mg, 0.51 mmol) andphenylboronic acid (75 mg, 0.62 mmol) in THF/water ({fraction (1/1)}, 4mL) is added Na₂CO₃ (219 mg, 2.06 mmol), triphenylphosphine (9 mg,{fraction (1/15)} mol %) and palladium acetate (1 mg, {fraction (1/135)}mol %). The mixture is heated at 80° C. overnight, the solvents areevaporated and the residue is purified by flash chromatography (gradientof CH₂Cl₂/MeOH) to give(2-biphenyl-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as ayellow solid (99 mg, 51%):¹H NMR (DMSO) δ 2.37 (3H, s), 6.82 (1H, s),7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d), 10.42(1H, s), 12.27 (1H, s); MS 378.2 (M+H)⁺

[0706] Method H(ii). To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol) inDMF (2 mL) is added CuI (1.1 mg, {fraction (1/50)} mol %), Pd(PPh₃)₂Cl₂(4.2 mg, {fraction (1/50)} mol %) and triethylamine (121 mg, 0.36 mmol).The mixture is heated at 120° C. overnight and the solvent isevaporated. The residue is triturated in ethyl acetate and theprecipitate is collected by filtration.

[0707] To the above precipitate suspended in THF (3 mL) is addedtetrabutylammonium fluoride (1M in THF, 1.1 eq). The reaction mixture isstirred at room temperature for two hours and the solvent is evaporated.The residue is purified by flash chromatography (gradient ofCH₂Cl₂/MeOH) to give[2-(4-ethynylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amineas a white solid (68 mg, 70%): ¹H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H,s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H,d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M+H)⁺

[0708] Method I above shows a general route for the preparation of thepresent compounds wherein ring D is a heteroaryl or heterocyclyl ringdirectly attached to the pyrimidine 2-position via a nitrogen atom.Displacement of the 2-chloro group, exemplified here using piperidine,may be carried out in a manner similar to that described in J. Med.Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). Thismethod is illustrated by the following procedure.

[0709] To a solution of(2-chloro-quinazolin-4-yl)-(1H-indazol-3-yl)-amine (1 equivalent,0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml) is added the desiredamine (3 equivalents). The resulting mixture is maintained at 100° C.for 6 h and then purified by reverse-phase HPLC.

[0710] Method J above shows the preparation of compounds of formula Vvia the displacement of a chloro group from an appropriately substitutedpyridyl ring. Method J(i) is a route for preparing compounds of formulaVa (see Indian J. Chem. Sect.B, 35, 8, 1996, 871-873). Method J(ii) is aroute for preparing compounds of formula Vb (see Bioorg. Med. Chem.,6,12, 1998, 2449-2458). For convenience, the chloropyridines 21 and 23 areshown with a phenyl substituent corresponding to Ring D of formula V. Itwould be apparent to one skilled in the art that Method J is also usefulfor preparing compounds of formula V wherein Ring D is heteroaryl,heterocyclyl, carbocyclyl or other aryl rings. Method J is illustratedby the following procedures.

[0711] Method J(i).(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine. To4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128)(0.53 g,-2.21 mmol) in diphenylether (5 mL) was added 3-amino-5-methylpyrazole(0.43 g, 4.42 mmol) and the mixture was heated at 200° C. overnight withstirring. To the cooled mixture was added petroleum ether (20 mL) andthe resulting crude precipitate was filtered and further washed withpetroleum ether. The crude solid was purified by flash chromatography(SiO₂, gradient DCM-MeOH) to give the title compound as a white solid:mp 242-244° C.; ¹H NMR (DMSO) δ 2.27(3H, s), 6.02(1H, s), 7.47(2H, d),7.53-7.40(2H, br m), 7.67(1H, m), 7.92(1H, m), 8.09(2H, d), 8.48(2H, m),9.20(1H, s), 12.17(1H, br s); IR (solid) 1584, 1559, 1554, 1483, 1447,1430, 1389; MS 301.2 (M+H)⁺

[0712] Method J(ii).(5-Methyl-2H-pyrazol-3-yl)-(3-phenyl-isoquinolin-1-yl)-amine. To1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121-128)(0.33 g,1.37 mmol) in dry DMF (5 mL) was added 3-amino-5-methylpyrazole (0.27g,2.74 mmol) and potassium carbonate (0.57g, 4.13 mmol) and the mixturewas heated under reflux for 6 hours. The mixture was cooled and the bulkof DMF was evaporated. The residue was extracted twice with ethylacetate and the combined organic layers were washed with brine, dried(MgSO₄), filtered and concentrated. The crude was purified by flashchromatography (SiO₂, gradient DCM-MeOH) to give the title compound as acolourless oil; ¹H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H,m), 7.52(2H, m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m),8.29(1H, s), 8.54 (1H, d); MS 301.2 (M+H)⁺

[0713] Method K shows a route for the preparation of compounds offormula VI. A versatile starting material is2,4,6-trichloro-[1,3,5]triazine 25 in which the chlorine substituentsmay be sequentially displaced. The displacement of one of the chlorinesby an aryl Grignard reagent or an aryl boronic acid is described in PCTpatent application WO 01/25220 and Helv. Chim. Acta, 33, 1365 (1950).The displacement of one of the chlorines by a heteroaryl ring isdescribed in WO 01/25220; J. Het. Chem., 11, 417 (1974); and Tetrahedron31, 1879 (1975). These reactions provide a2,4-dichloro-(6-substituted)(1,3,5]triazine 26 that is a usefulintermediate for the preparation of compounds of formula VI.Alternatively, intermediate 26 may be obtained by constructing thetriazine ring by known methods. See US patent 2,832,779; and US patent2,691020 together with J. Am. Chem. Soc. 60, 1656 (1938). In turn, oneof the chlorines of 26 may be displaced as described above to provide2-chloro-(4,6-disubstituted)[1,3,5]triazine 27. The treatment of 27 withan appropriate aminopyrazole provides the desired compound of formulaVI.

[0714] Method L shows a route for preparing compounds of formula VII.For illustration purposes the trifluoromethylchalcone 28 is used as astarting material; however, it would be apparent to one skilled in theart that other rings may be used in place of the trifluoromethylphenyland phenyl rings of compound 28. Substituted chalcones may be preparedby known methods, for example as described in the Indian J. Chemistry,32B, 449 (1993). Condensation of a chalcone with urea provides thepyrimidinone 29, which may be treated with POCl₃ to give thechloropyrimidine 30. See J. Chem. Eng. Data, 30(4)512 (1985) and Egypt.J. Chem., 37(3), 283 (1994). In an alternative approach to compound 30,one of the aryl rings attached to the pyrimidine is introduced bydisplacement of of the 4-chloro group of2,4-dichloro-(6-aryl)-pyrimidine by an aryl boronic acid using apalladium catalyst such as (Ph₃P)₄Pd in the presence of a base such assodium carbonate as described in Bioorg. Med. Lett., 9(7), 1057 (1999).Displacement of the chlorine of compound 30 by an appropriateaminopyrazole provides compounds of this invention, such as 31. The laststep of this method is illustrated by the following procedure.

[0715][4-(4-Methylpiperidin-1-yl)-pyrimidin-2-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine(prepared using a procedure similar to the one reported in Eur. J. Med.Chem., 26(7)729(1991))(222 mg, 1.05 mmol) in BuOH (5 mL) was added3-amino-5-methyl-2H-pyrazole (305mg, 3.15 mmol) and the reaction mixturewas then heated under reflux overnight. The solvent was evaporated andthe residue dissolved in a mixture ethanol/water (⅓, 4 mL). Potassiumcarbonate (57 mg, 0.41 mmol) was added and the mixture was stirred atroom temperature for 2 hours. The resulting suspension was filtered,washed with water twice and rinsed with ether twice to give the titlecompound as a white solid (143 mg, 50%): mp 193-195° C.; ¹H NMR (DMSO) δ0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t),4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s), 11.71 (1H,s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3(M+H)⁺.

[0716] Method M provides routes for obtaining compounds of formula VIII.A general procedure for displacing the chlorine of a4-chloro-6-substituted-pyridazine, 32, with an appropriately substitutedpyrazole to provide VIIIa is described in J. Het. Chem., 20, 1473(1983). Analogous reactions may be carried out as follows: (a) with3-chloro-5-substituted-pyridazine, 33, to provide VI11b is described inJ. Med. Chem., 41(3), 311 (1998); (b) with5-chloro-3-substituted-[1,2,4]triazine, 34, to provide VIIIc isdescribed in Heterocycles, 26(12), 3259 (1987); and (c) with3-chloro-5-substituted-[1,2,4]triazine, 35, to provide VIIId isdescribed in Pol. J. Chem., 57, 7, (1983); Indian J. Chem. Sect. B, 26,496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternativeprocedure to compounds of formula VIIIc is described in Indian J. Chem.Sect. B, 29(5), 435 (1990).

[0717] Compounds of formula IX are prepared by methods substantiallysimilar to those described above for the pyrazole-containing compoundsof formula I. Methods A-J may be used to prepare the triazole-containingcompounds of formula IX by replacing the amino-pyrazole compound with anamino-triazole compound. Such methods are specifically exemplified bySynthetic Examples 415-422 set forth below. The amino-triazoleintermediate may be obtained by methods described in J. Org. Chem. USSR,27, 952-957 (1991).

[0718] Certain synthetic intermediates that are useful for preparing theprotein kinase inhibitors of this invention are new. Accordingly,another aspect of this invention relates to a 3-aminoindazole compoundof formula A:

[0719] where R¹⁰ is one to three substituents that are eachindependently selected from fluoro, bromo, C₁₋₆ haloalkyl, nitro, or1-pyrrolyl. Examples of such compounds include the following:

[0720] Another aspect of this invention relates to a 4-chloropyrimidinecompound of formula B:

[0721] wherein R^(x) and R^(y) are as defined above; R¹ is selected fromCl, F, CF₃, CN, or NO₂; and is one to three substituents that are eachindependently selected from H, Cl, F, CF₃, NO₂, or CN; provided that R¹and R⁵ are not simultaneously Cl. Examples of compounds of formula B areshown below:

[0722] Another aspect of this invention relates to compounds of formulaC:

[0723] wherein R^(x), R^(y), R², and R^(2′) are as defined above.Examples of compounds of formula C are shown below:

[0724] Yet another aspect of this invention relates to compounds offormula D:

[0725] where R⁵, R^(x) and R^(y) are as def ined above. Examples offormula D compounds and other useful pyrimidinone intermediates areshown below:

[0726] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

[0727] The following HPLC methods were used in the analysis of thecompounds as specified in the Synthetic Examples set forth below. Asused herein, the term “R_(t)” refers to the retention time observed forthe compound using the HPLC method specified.

[0728] HPLC-Method A:

[0729] Column: C18, 3 um, 2.1×50 mm, “Lighting” by Jones Chromatography.

[0730] Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100%acetonitrile for 1.4 min and return to initial conditions. Total runtime 7.0 min. Flow rate: 0.8 mL/min.

[0731] HPLC-Method B:

[0732] Column: C18, 5 um, 4.6×150 mm “Dynamax” by Rainin Gradient: 100%water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile(containing 0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 minand return to initial conditions. Total run time 31.5 min. Flow rate:1.0 mL/min.

[0733] HPLC-Method C:

[0734] Column: Cyano, 5 um, 4.6×150 mm “Microsorb” by Varian.

[0735] Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1%TFA) to 50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA)over 20 min, hold for 8.0 min and return to initial conditions. Totalrun time 30 min. Flow rate: 1.0 mL/min.

[0736] HPLC-Method D:

[0737] Column: Waters (YMC) ODS-AQ 2.0×50 mm, S5, 120A.

[0738] Gradient: 90% water (0.2% Formic acid), 10% acetonitrile(containing 0.1% Formic acid) to 10% water (0.1% formic acid), 90%acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for 0.8min and return to initial conditions. Total run time 7.0 min.

[0739] Flow rate: 1.0 mL/min.

[0740] HPLC-Method E:

[0741] Column: 50×2.0 mm Hypersil C18 BDS;5 μm Gradient: elution 100%water (0.1% TFA), to 5% water (0.1% TFA), 95% acetonitrile (containing0.1% TFA) over 2.1 min, returning to initial conditions after 2.3 min.

[0742] Flow rate: 1 mL/min.

EXAMPLE 1[2-(2-Clorophenyl)-5,6-dimethylpyrimidin-4-yl-(5-Methyl-2H-pyrazol-3-yl)-amine(II-1)

[0743]¹HNMR (500 MHz, DMSO-d6) δ 10.4 (s, br, 1H), 7.74 (m, 2H), 7.68(m, 1H), 7.60 (m, 1H), 6.39 (s, 1H), 2.52 (s, 3H), 2.30 (s, 3H), 2.22(s, 3H); MS 314.1 (M+H).

EXAMPLE 2[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-2)

[0744] Prepared in 30% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.72 (m, 4H),1.91 (m, 2H), 3.02 (m, 4H), 7.05 (t, 1H), 7.33 (t, 1H), 7.39 (m, 1H),7.47 (d, 1H), 7.55 (m, 3H), 7.59 (d, 1H), 10.4 (m, 1H), 13.11 (br. s,1H); EI−MS 390.2 (M+H); HPLC-Method A, R_(t) 2.99 min.

Example 3(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4d]pyrimidin-4-yl]-amine(II-3)

[0745] compound II-18 (90 mg, 0.17 mmol) was treated with an equalweight of Pd/C (10%) in 4.4% formic acid in MeOH at room temperature for14 h. The mixture was filtered through celite, the filtrate wasevaporated, and crude product was purified by HPLC to provide 18 mg(24%) of the desired product as pale yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 12.9 (s, 1H), 9.51 (s, 1H), 9.26 (s, 2H), 7.72 (d, 1H), 7.63(t, 1H), 7.58 (t, 1H), 7.49 (m, 2H), 7.21 (td, 1H), 7.15 (dd, 1H), 4.24(s, 2H), 3.56 (m, 2H), 2.95 (m, 2H) ppm. MS (ES+): m/e=429.22 (M+H);HPLC-Method A, R_(t) 2.88 min.

EXAMPLE 4[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-4)

[0746] Prepared in 52% yield to afford a white solid. ¹HNMR (500 MHz,DMSO-d6) δ 1.72 (m, 4H), 1.92 (m, 2H), 3.00 (m, 4H), 7.02 (td, 1H), 7.20(dd, 1H), 7.40 (m, 1H), 7.42 (d, 1H), 7.52 (m, 3H), 10.5 (m, 1H), 13.50(br. s, 1H); EI−MS 408.2 (M+H); HPLC-Method A, R_(t) 3.00 min.

EXAMPLE 5[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-5)

[0747] Prepared in 51% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.71 (m, 4H),1.91 (m, 2H), 3.01 (m, 4H), 7.24 (td, 1H), 7.41 (m, 2H), 7.54 (m, 4H),10.5 (m, 1H), 13.1 (br. s, 1H); EI−MS 408.2 (M+H); HPLC-Method A, R_(t)3.05 min.

EXAMPLE 6[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-6)

[0748] Prepared according to Method C in 72% yield. ¹HNMR (500 MHz,DMSO-d6) δ 1.72 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.31 (m, 2H), 7.41(m, 1H), 7.54 (m, 3H), 10.5 (m, 1H), 13.6 (br. s, 1H); EI−MS 426.2(M+H); HPLC-Method A, R_(t) 3.21 min.

EXAMPLE 7(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-7)

[0749] Prepared in 62% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.5 (s, br,1H), 10.1 (s, br, 1H), 7.75 (m, 4H), 7.33 (d, 1H), 7.17 (dd, 1H), 7.00(td, 1H), 2.80 (m, 2H), 2.71 (m, 2H), 1.89 (br, 4H) ppm; LC−MS(ES+)428.44 (M+H), (ES−)426.43 (M−H); HPLC-Method A, R_(t) 3.02 min.

EXAMPLE 8(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-8)

[0750] Prepared in 53% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.1 (s, 1H),10.2 (s, br, 1H), 7.75 (m, 4H), 7.50 (dd, 1H), 7.27 (dd, 1H), 7.21 (td,1H), 2.80 (m, 2H), 2.72 (m, 2H), 1.88 (m, 4H) ppm; MS (ES+) 428.43(M+H), (ES−)426.43 (M−H); HPLC-Method A, R_(t) 3.01 min.

EXAMPLE 9(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-9)

[0751] Prepared in 37% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.7 (s, 1H),10.2 (s, br, 1H), 7.80 (d, 1H), 7.76 (t, 1H), 7.69 (m, 2H), 7.31 (t,1H), 7.18 (d, 1H), 2.81 (t, br, 2H), 2.72 (t, br, 2H), 1.90 (m, 4H) ppm;MS (ES₊)446.42 (M+H), (ES−)444.37 (M−H); HPLC-Method A, R_(t) 3.09 min.

EXAMPLE 10(5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-10)

[0752] Prepared by Method C in ethanol in 35% yield. ¹HNMR (500 MHz,DMSO-d6) δ 13.2 (s, 1H), 10.1 (s, br, 1H), 8.01 (s, 1H), 7.76 (d, 1H),7.66 (m, 4H), 7.57 (d, 1H), 2.79 (m, 2H), 2.73 (m, 2H), 1.89 (m, 4H)ppm. MS (ES+)478.45 (M+H), (ES−)476.42 (M−H); HPLC-Method A, R_(t) 3.21min.

EXAMPLE 11(5,7-difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-11)

[0753] Prepared in 60% yield. White solid. ¹HNMR (500 MHz, DMSO-d6) δ1.72 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.15 (dd, 1H), 7.30 (td, 1H),7.66 (m, 2H), 7.72 (t, 1H), 7.78 (d, 1H), 10.2 (m, 1H), 13.5 (br. s,1H); EI−MS 460.2 (M+H); HPLC-Method A, R_(t) 3.13 min.

EXAMPLE 12(6-Benzyl-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-fluoro-1H-indazol-3-yl)-amine(II-12)

[0754] Prepared in 49% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.8 (s, 1H),9.11 (s, 1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.53 (t, 1H), 7.44 (m, 4H),7.37 (t, 2H), 7.29 (t, 1H), 7.19 (m, 2H), 3.78 (s, 2H), 3.61 (s, 2H),2.81 (s, br, 4H) ppm; LC−MS (ES+) 519.24 (M+H); HPLC-Method A, R_(t)3.11 min.

EXAMPLE 13(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-13):

[0755] Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.70 (m, 4H),1.90 (m, 2H), 3.00 (m, 4H), 7.01 (t, 1H), 7.30 (td, 1H), 7.44 (d, 1H),7.49 (d, 1H), 7.68 (m, 3H), 7.77 (d, 1H), 10.01 (m, 1H), 12.83 (s, 1H);EI−MS 424.2 (M+H); HPLC-Method A, R_(t) 3.17 min.

EXAMPLE 14(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-14)

[0756] Prepared in 78% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.71 (m, 4H),1.91 (m, 2H), 3.00 (m, 4H), 6.98 (td, 1H), 7.16 (dd, 1H), 7.31 (d, 1H),7.68 (m, 3H), 7.77 (d, 1H), 10.25 (m, 1H), 13.40 (br. s, 1H); EI−MS442.2 (M+H); HPLC-Method A, R_(t) 3.12 min.

EXAMPLE 15(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-15)

[0757] Prepared in 63% yield. ¹HNMR (500 MHz, DMSO-d6)δ 1.71 (m, 4H),1.91 (m, 2H), 3.00 (m, 4H), 7.20 (td, 1H), 7.25 (dd, 1H), 7.49 (dd, 1H),7.69 (br. t, 2H), 7.74 (m, 1H), 7.79 (d, 1H), 10.35 (m, 1H), 13.00 (br.s, 1H); EI−MS 442.2 (M+H); HPLC-Method A, R_(t) 3.21 min.

EXAMPLE 16(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine(II-16)

[0758] A solution of compound II-12 (45mg, 0.087 mmol) in methanol (4.4%HCOOH) was treated with an equal weight of Pd/C (10%) at roomtemperature for 14 h. The mixture was filtered through celite, thefiltrate evaporated, and the crude product was purified by preparativeHPLC to provide 15 mg (41%) of the desired product as yellow solid.¹HNMR (500 MHz, DMSO-d6) δ 12.9 (s, 1H), 9.52 (s, 1H), 9.32 (s, 2H,TFA—OH), 7.72 (d, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.21 (m, 1H), 7.15(m, 1H), 4.31 (s, 2H), 3.55 (s, 2H), 3.00 (m, 2H) ppm; LC−MS (ES+)429.20 (M+H); HPLC-Method A, R_(t) 2.79 min.

EXAMPLE 17(1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-17)

[0759] Prepared in 58% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H),10.3 (s, br, 1H), 7.74 (m, 4H), 7.51 (d, 1H), 7.47 (d, 1H), 7.32 (t,1H), 7.03 (t, 1H), 2.82 (m, 2H), 2.73 (m, 2H), 1.90 (m, 4H) ppm; LC−MS(ES+)410.21 (M+H); HPLC-Method A, R_(t) 2.99 min.

EXAMPLE 18(7-Benzyl-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-fluoro-1H-indazol-3-yl)-amine(II-18)

[0760] Prepared from compound B11 in 92% yield. ¹HNMR (500 MHz, DMSO-d6)δ 12.9 (s, 1H), 10.5 (s, br, 1H), 9.58 (s, 1H, TFA—OH), 7.71 (d, 1H),7.52 (m, 9H), 7.19 (m, 2H), 4.57 (s, 2H), 4.20 (m, 2H), 3.70 (m, 2H),3.00 (m, 2H) ppm; LC−MS (ES+) 519.23 (M+H); HPLC-Method A, R_(t) 3.23min.

EXAMPLE 19(1H-Indazol-3-yl)-[6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-19)

[0761] Prepared in 42% yield. Melting point 235-237° C.; ¹HNMR (500 MHz,DMSO) δ 2.44 (3H, s), 7.09 (1H, J=7.5 Hz, t), 7.40 (1H, J=7.1 Hz, t),7.49 (1H, J=8.3 Hz, d), 7.70 (3H, m), 7.79 (1H, J=7.3 Hz, t), 7.87 (1H,J=8.3 Hz, d), 8.03 (1H, J=7.7 Hz, d), 10.3 (1H, s), 12.6 (1H, s) ppm;HPLC-Method A, R_(t) 2.958 min; MS (FIA)370.2 (M+H)⁺.

EXAMPLE 20(1H-Indazol-3-yl)-[6-phenyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-20)

[0762] Prepared in 32% yield. ¹HNMR (500 MHz, DMSO) δ 6.94 (1H, J=7.4Hz, t), 7.24 (1H, J=7.4 Hz, t), 7.33 (1H, J=8.4 Hz, d), 7.42 (3H, m),7.57 (1H, J=7.3 Hz, t), 7.68 (2H, m), 7.75 (1H, J=7.9 Hz, d), 7.93 (3H,m), 8.18 (1H, br s), 10.45 (1H, br s), 12.5 (1H, br s) ppm; HPLC-MethodA, R_(t) 4.0 min; MS (FIA)432.2 (M+H)⁺.

EXAMPLE 21(1H-Indazol-3-yl)-[6-(pyridin-4-yl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-21)

[0763] Prepared in 12% yield. ¹HNMR (500 MHz, DMSO) δ 7.16 (1H, J=7.4Hz, t), 7.46 (1H, J=7.6 Hz, t), 7.56 (1H, J=8.3 Hz, d), 7.80 (1H, J=7.2Hz, t), 7.90 (2H, m), 7.97 (1H, J=7.8 Hz, d), 8.09 (1H, br), 8.22 (2H,J=4.9 Hz, d), 8.45 (1H, br s), 8.93 (2H, J=4.8 Hz, d), 10.9 (1H, br s),12.8 (1H, br s) ppm; HPLC-Method A, R_(t) 3.307 min; MS (FIA)433.2(M+H)⁺

EXAMPLE 22(1H-Indazol-3-yl)-[6-(pyridin-2-yl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-22)

[0764] Prepared in 42% yield. ¹HNMR (500 MHz, DMSO) δ 7.07 (1H, J=7.4Hz, t), 7.36 (1H, J=7.4 Hz, t), 7.46 (1H, J=7.4 Hz, d), 7.53 (1H, J=5.0Hz, t), 7.70 (1H, J=7.4 Hz, t), 7.79 (1H, J=7.1 Hz, t), 7.83 (1H, J=7.4Hz, d), 7.88 (1H, J=7.8 Hz, d), 7.97 (1H, J=7.7 Hz, t), 8.02 (1H, J=5.5Hz, br d), 8.36 (1H, J=7.8 Hz, d), 8.75 (2H, J=4.1 Hz, d), 10.5 (1H, brs), 12.7 (1H, br s) ppm; HPLC-Method A, R_(t) 3.677 min; MS (FIA)433.2(M+H)⁺.

EXAMPLE 23[6-(2-Chlorophenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-23):

[0765] Prepared in 44% yield; ¹HNMR (500 MHz, DMSO) δ 7.08 (1H, J=7.5Hz, t), 7.37 (1H, J=7.5 Hz, t), 7.45 (1H, J=8.4 Hz, d), 7.51 (2H, m),7.61 (1H, J=7.4, 1.9 Hz, dd), 7.69 (2H, m), 7.79 (2H, J=4.0 Hz, d), 7.86(3H, J=7.8 Hz, d), 8.04 (2H, J=6.2 Hz, br d), 10.7 (1H, br s), 12.6 (1H,br s) ppm; HPLC-Method A, R_(t) 3.552 min; MS (FIA)466.2 (M+H)⁺.

EXAMPLE 24[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-24)

[0766] Prepared in 35% yield; mp 183-186° C.; ¹HNMR (500 MHz, DMSO) δ2.14 (3H, s), 2.27 (3H, s), 6.85 (1H, J=7.5 Hz, t), 7.15 (1H, J=7.6 Hz,t), 7.32 (3H, m), 7.38 (1H, J=7.5 Hz, t), 7.42 (1H, J=7.4 Hz, t), 7.53(1H, J=7.6 Hz, d), 8.88 (1H, s), 12.5 (1H, s) ppm; HPLC-Method A, R_(t)2.889 min.; MS (FIA) 384.2 (M+H)′.

EXAMPLE 25[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-25)

[0767] Prepared in 44% yield. Melting point 160-163° C.; ¹HNMR (500 MHz,DMSO) δ 2.27 (3H, s), 2.40 (3H, s), 7.16 (2H, m), 7.44 (2H, m), 7.52(1H, J=7.4 Hz, t), 7.57 (1H, J=7.4 Hz, t), 7.67 (1H, J=7.8 Hz, d), 9.03(1H, s), 12.75 (1H, s) ppm; HPLC-Method A, R_(t) 2.790 min; MS(FIA)402.2 (M+H)⁺.

EXAMPLE 26[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yll-(1H-indazol-3-yl)-amine(II-26)

[0768] Prepared in 30% yield. ¹HNMR (500 MHz, DMSO) δ 2.14 (3H, s), 2.33(3H, s), 6.84 (1H, J=7.4 Hz, t), 7.13 (1H, J=7.4 Hz, t), 7.19 (1H, J=6.9Hz, br t), 7.27 (1H, J=7.4 Hz, d), 7.32 (3H, br m), 7.37 (1H, J=7.1 Hz,d), 10.0 (1H, br), 12.8 (1H, br s) ppm; δ 2.919 min; MS (FIA)350.1(M+H)⁺.

EXAMPLE 27[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-27)

[0769] Prepared in 92% yield. ¹HNMR (500 MHz, DMSO) δ 2.33 (3H, s), 2.50(3H, s), 6.97 (1H, m), 7.15 (1H, m), 7.30 (1H, J=8.1 Hz, d), 7.65 (3H,m), 7.76 (1H, J=7.5 Hz, d), 10.0 (1H, s), 13.4 (1H, s) ppm; HPLC-MethodA, R_(t) 3.053 min; MS (FIA)402.2 (M+H)^(+.)

EXAMPLE 28(5,7-Difluoro-1H-indazol-3-yl)-[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-28)

[0770] Prepared in 50% yield. ¹HNMR (500 MHz, DMSO) δ 2.42 (3H, s), 2.63(3H, s), 7.22 (1H, J=7.6 Hz, d), 7.38 (1H, J=9.3, 1.7 Hz, dt), 7.71 (1H,m), 7.75 (1H, J=7.0 Hz, d), 7.79 (1H, J=6.7 Hz, d), 7.86 (1H, J=8.0 Hz,d), 10.0 (1H, s), 13.2 (1H, s) ppm; HPLC-Method A, R_(t) 3.111 min; MS(FIA)420.2 (M+H)⁺.

EXAMPLE 29[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-29)

[0771] Prepared in 58% yield. ¹HNMR (500 MHz, DMSO) δ 2.47 (3H, s), 2.66(3H, s), 7.44 (2H, m), 7.53 (1H, m), 7.64 (3H, m), 10.4 (1H, br), 13.8(1H, br s) ppm; HPLC-Method A, R_(t) 2.921 min; MS (FIA)386.1 (M+H)⁺.

EXAMPLE 30[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-30)

[0772] Prepared in 70% yield. ¹HNMR (500 MHz, DMSO) δ 2.35 (3H, s), 2.51(3H, s), 7.03 (1H, J=7.8, 4.4 Hz, dt), 7.22 (1H, m), 7.33 (1H, J=7.4 Hz,t), 7.42 (1H, m), 9.19 (1H, s), 13.3 (1H, s) ppm; HPLC-Method A, R_(t)2.859 min; MS (FIA)368.2 (M+H)⁺.

EXAMPLE 31[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-31)

[0773] Prepared in 86% yield. ¹HNMR (500 MHz, DMSO) δ 2.49 (3H, s), 2.68(3H, s), 7.38 (1H, J=9.0 Hz, t), 7.54 (2H, m), 7.67 (4H, m), 10.5 (1H,br), 13.2 (1H, br s) ppm; HPLC-Method A, R_(t) 2.850 min; MS (FIA)368.1(M+H)⁺.

EXAMPLE 32[2-(2,4-Dichlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-32)

[0774] Prepared in 52% yield. ¹HNMR (500 MHz, DMSO) δ 2.46 (3H, s), 2.64(3H, s), 7.16 (1H, J=7.5 Hz, t), 7.46 (1H, J=7.6 Hz, t), 7.61 (2H, m),7.68 (2H, J=8.2 Hz, d), 7.82 (1H, m), 10.2 (1H, br), 13.0 (1H, br s)ppm; HPLC-Method A, R_(t) 2.983 min; MS (FIA)384.1 (M+H).

EXAMPLE 33(5-Methyl-2H-pyrazol-3-yl)-[2-(2-methylphenyl)-quinazolin-4-yl]-amine(II-33)

[0775]¹HNMR (DMSO) δ 1.21 (3H,s), 2.25 (3H, s), 6.53 (1H, s), 7.38 (4H,m), 7.62 (1H, d), 7.73 (1H, d), 7.81 (1H, d), 7.89 (1H, t), 8.70 (1H,s), 12.20 (1H, s); MS 316.3 (M+H)⁺.

EXAMPLE 34

[0776][2-(2,4-Difluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-34)

[0777]¹HNMR (500 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.58(d, 1H), 7.97 (m, 1H), 8.36 (m, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 6.62(s, 1H), 2.30 (s, 3H); MS 338.07 (M+H).

EXAMPLE 35[2-(2,5-Dimethoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-35)

[0778]¹HNMR (500 MHz, DMSO-d6) δ 12.5 (br s, 1H), 8.68 (br, 1H), 7.92(t, J=7.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.45(s, 1H), 7.14 (m, 2H), 6.51 (s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 2.14(s, 3H); MS 362.2 (M+H).

EXAMPLE 36[2-(2-Chlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-36)

[0779]¹HNMR (500 MHz, DMSO-d6) δ 11.8 (br, 1H), 8.80 (d, J=8.3 Hz, 1H),8.00 (t, J=7.6 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.78 (m, 2H), 7.67 (d,J=7.8 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H), 7.55 (t, J=7.4 Hz, 1H), 6.56 (s,1H), 2.18 (s, 3H); MS 336.1 (M+H).

EXAMPLE 37[2-(2-Methoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-37)

[0780]¹HNMR (500 MHz, DMSO-d6) δ 8.78 (s, br, 1H), 8.00 (t, J=7.4 Hz,1H), 7.90 (m, 2H), 7.74 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.3 Hz, 1H), 7.30(d, J=8.4 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.58 (s, br, 1H), 3.90 (s.3H), 2.21 (s, 3H); MS 332.1 (M+H).

EXAMPLE 38[2-(2,6-Dimethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-38)

[0781]¹HNMR (500 MHz, DMSO-d6) δ 12.2 (s, br, 2H), 8.88 (d, J=7.7 Hz,1H), 8.05 (t, J=7.7 Hz, 1H), 7.80 (m, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.21(d, J=7.7 Hz, 2H), 6.36 (s, 1H), 2.16 (s, 3H), 2.15 (s, 6H); MS 330.1(M+H)

EXAMPLE 39(2-(2-Acetylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-39)

[0782]¹HNMR (500 MHz, DMSO-d6) δ 12.35 (s, br, 1H), 8.93 (d, J=8.4 Hz,1H), 8.37 (d, J=8.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 8.11 (t, J=8.0 Hz,2H), 7.89 (m, 2H), 7.77 (m, 2H), 6.93 (s, 1H), 2.33 (s, 3H), 2.04 (s,3H) MS 344.1 (M+H).

EXAMPLE 40[2-(2,3-Dimethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-40)

[0783]¹HNMR (500 MHz, DMSO-d6) δ 12.6 (s, br, 1H), 12.1 (s, br, 1H),8.91 (d, J=7.7 Hz, 1H), 8.14 (t, J=7.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),7.89 (t, J=7.7 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H),7.42 (t, J=7.6 Hz, 1H), 6.60 (s, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 2.32(s, 3H); MS 330.1 (M+H).

EXAMPLE 41(5-Methyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-41)

[0784]¹HNMR (500 MHz, DMSO-d6) δ 12.3 (s, 1H), 10.5 (s, 1H), 8.77 (d,J=8.2 Hz, 1H), 7.92 (m, 2H), 7.85 (m, 3H), 7.56 (t, J=8.1 Hz, 1H), 7.67(t, J=7.4 Hz, 1H), 6.63 (s, 1H), 2.27 (s, 3H); MS 370.1 (M+H).

EXAMPLE 42[2-(2-Ethylphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-42)

[0785]¹HNMR (500 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.02 (s, br, 1H), 7.82(d, J=8.4 Hz, 1H), 7.77 (m, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.54 (m, 1H),7.41 (m, 2H), 6.40 (s, 1H), 2.75 (q, J=7.1 Hz, 2H), 2.17 (s, 3H), 0.99(t, J=7.5 Hz, 3H); MS 330.1 (M+H).

EXAMPLE 43(2-Biphenyl-2-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(II-43)

[0786]¹HNMR (500 MHz, DMSO-d6) δ 8.76 (d, J=7.6 Hz, 1H), 8.04 (m, 1H),7.75 (m, 6H), 7.30 (m, 5H), 5.34 (s, 1H), 2.14 (s, 3H); MS 378.2 (M+H).

EXAMPLE 44[2-(2-Hydroxyphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-44)

[0787]¹HNMR (500 MHz, DMSO-d6) δ 10.9 (s, br, 1H), 8.62 (d, J=8.2 Hz,1H), 8.28 (d, J=7.9 Hz, 1H), 7.87 (m, 2H), 7.60 (t, J=7.9 Hz, 1H), 7.37(t, J=7.8 Hz, 1H), 6.92 (m, 2H), 6.45 (s, 1H), 2.27 (s, 3H); MS 318.1(M+H).

EXAMPLE 45[2-(2-Ethoxyphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-45)

[0788]¹HNMR (500 MHz, DMSO-d6) δ 12.1 (s, br, 1H), 8.75 (d, J=8.3 Hz,1H), 7.97 (t, J=7.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.78 (d, J=7.5 Hz,1H), 7.70 (t, J=7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.22 (d, J=8.4 Hz,1H), 7.12 (t, J=7.6 Hz, 1H), 6.55 (s, 1H), 4.11 (q, J=6.9 Hz, 2H), 2.16(s, 3H), 1.22 (t, J=6.9 Hz, 3H); MS 346.1 (M+H).

EXAMPLE 46[5-(Thiophen-2-yl)-2H-pyrazol-3-yl]-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-46)

[0789]¹HNMR (500 MHz, DMSO-d6) δ 8.04 (d, J=8.3 Hz, 1H), 8.05 (dd,J=7.3, 8.2 Hz, 1H), 7.93 (d, J=6.5 Hz, 1H), 7.81 (m, 5H), 7.34 (d, J=5.0Hz, 1H), 7.25 (m, 1H), 7.00 (m, 1H), 6.87 (s, 1H); MS 438.1 (M+H).

EXAMPLE 47[4-(Thiophen-2-yl)-2H-pyrazol-3-yl]-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-47)

[0790] Prepared according to Method B. ¹HNMR (500 MHz, DMSO-d6) δ 6.97(m, 1H), 7.08 (m, 1H), 7.27 (m, 1H), 7.36 (m, 1H), 7.66 (m, 2H), 7.77(m, 3H), 7.83 (m, 1H), 8.00 (m, 1H), 8.18 (s, 1H), 8.62 (d, J=8.2 Hz,1H), 10.7 (br. S, 1H); EI−MS 438.1 (M+H); HPLC-Method A, R_(t) 2.97 min.

EXAMPLE 48(4-Phenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-48)

[0791] Prepared according to Method B. ¹HNMR (500 MHz, DMSO-d6) δ 7.05(br. s, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.25 (m, 3H), 7.43 (m, 2H), 7.60(m, 2H), 7.73 (m, 2H), 7.80 (d, 1H), 7.95 (m, 1H), 8.12 (br. s, 1H),8.60 (m, 1H), 10.6 (br. S, 1H); EI−MS 432.2 (M+H); HPLC-Method A, R_(t)3.04 min.

EXAMPLE 49(5-tert-Butyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-49)

[0792]¹HNMR (500 MHz, DMSO-d6) δ 8.76 (d, J=8.3 Hz, 1H), 7.94 (m, 2H),7.79 (m, 4H), 7.70 (t, J=7.6 Hz, 1H), 6.51 (s, 1H), 1.16 (s, 9H); MS412.2 (M+H).

EXAMPLE 50(5-Phenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-50)

[0793]¹HNMR (500 MHz, DMSO-d6) δ 7.09 (s, 1H), 7.36 (td, J=7.8, 1.1 Hz,1H), 7.46 (t, J=7.8 Hz, 2H), 7.65 (br. d, J=8.1 Hz, 2H), 7.78 (m, 2H),7.90 (m, 4H), 7.95 (d, J=7.7 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 8.81 (d,J=8.6 Hz, 1H), 11.29 (br. s, 1H); EI−MS 432.1 (M+H); HPLC-Method A,R_(t) 3.24 min.

EXAMPLE 51(4,5-Diphenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-51)

[0794]¹HNMR (500 MHz, DMSO-d6) δ 7.13 (m, 1H), 7.18 (m, 5H), 7.36 (m,5H), 7.62 (m, 3H), 7.73 (m, 2H), 7.85 (m, 1H), 8.48 (d, J=8.7 Hz, 1H),10.02 (s, 1H), 13.19 (s, 1H); EI−MS 508.2 (M+H); HPLC-Method A, R_(t)3.39 min.

EXAMPLE 52(4-Carbamoyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yll-amine(II-52)

[0795] Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6): δ 12.85 (s, 1H),12.77 (s, 1H), 11.80 (s, 1H), 10.80 (s, 1H), 8.35-7.42 (m, 9H); MS399.13 (M+H) HPLC-Method A, R_(t) 2.782 min.

EXAMPLE 53(2H-Pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-53)

[0796] Prepared in 38% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H),10.65 (s, 1H), 8.75 (d, 1H), 7.91-7.68 (m, 8H), 6.87 (s, 1H). MS:(M+H)356.17. HPLC-Method A, R_(t) 2.798 min.

EXAMPLE 54(5-Hydroxy-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-54)

[0797] Prepared in 36% yield; ¹HNMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H),8.75 (s, 1H), 8.03-7.75 (m, 9H), 5.97 (s, 1H); MS 372.18 (M+H);HPLC-Method A, R_(t) 2.766 min.

EXAMPLE 55(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-55):

[0798] Prepared in 30% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H),10.45 (s, 1H), 8.68 (s, 1H), 7.89-7.45 (m, 8H), 6.48 (s, 1H), 0.89 (m,2H), 0.62 (s, 2H). MS 396.18 (M+H); HPLC-Method A, R_(t) 3.069 min.

EXAMPLE 56(5-Methoxymethyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-56)

[0799] Prepared in 33% yield; ¹HNMR (500 MHz, DMSO-d6)δ 12.51 (s, 1H),10.48 (s, 1H), 8.60 (s, 1H), 7.81-7.55 (m, 7H), 6.71 (s, 1H), 4.28 (s,2H), 3.18 (s, 3H). MS 400.19 (M+H): HPLC-Method A, R_(t) 2.881 min.

EXAMPLE 57(1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-57)

[0800] Prepared to afford 51 mg (78% yield) as pale yellow solid. ¹HNMR(500 MHz, DMSO-d6)612.7 (s, 1H), 10.4 (s, 1H), 8.55 (d, 1H), 7.81 (t,1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.46 (m, 4H), 7.36 (d,1H), 7.22 (t, 1H), 6.91 (t, 1H) ppm; LC−MS (ES+)406.16 (M+H),(ES−)404.19 (M-H); HPLC-Method A, R_(t) 3.00 min.

EXAMPLE 58(4-Chloro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-58)

[0801] Prepared in DMF (70% yield) as pale yellow solid. ¹HNMR (500 MHz,DMSO-d6)613.3 (s, br, 1H), 10.9 (s, br, 1H), 8.60 (d, 1H), 7.97 (t, 1H),7.81 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.63 (dd, 1H), 7.57 (m, 2H),7.43 (d, 1H), 7.28 (dd, 1H), 7.08 (d, 1H) ppm; LC−MS (ES+)440.10 (M+H),(ES−)438.12 (M−H); HPLC-Method A, R_(t) 3.08 min.

EXAMPLE 59(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-59)

[0802] Prepared in DMF (34% yield) as pale yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.0 (s, 1H), 10.6 (s, 1H), 8.72 (d, 1H), 7.99 (t, 1H), 7.89(d, 1H), 7.79 (d, 1H), 7.75 (t, 1H), 7.68 (m, 3H), 7.56 (dd, 1H), 7.39(d, 1H), 7.28 (t, 1H) ppm; LC−MS (ES+)424.12 (M+H), (ES−) m/e=422.13(M−H); HPLC-Method A, R_(t) 3.05 min.

EXAMPLE 60(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-60)

[0803] Prepared in DMF (51% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.4 (s, 1H), 10.6 (s, 1H), 8.68 (d, 1H), 7.95 (t, 1H), 7.85(d, 1H), 7.72 (m, 2H), 7.63 (m, 2H), 7.58 (m, 1H), 7.43 (d, 1H), 7.18(dd, 1H), 7.00 (m, 1H) ppm; LC−MS (ES+)424.11 (M+H), (ES−)422.15 (M−H);HPLC-Method A, R_(t) 3.06 min.

EXAMPLE 61(5-Methyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-61)

[0804] Prepared in DMF (81% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.0 (s, br, 1H), 8.79 (br, 1H), 8.11 (br, 1H), 7.96 (d, 1H),7.82 (m, 5H), 7.46 (s, 1H), 7.41 (d, 1H), 7.20 (d, 1H), 2.33 (s, 3H)ppm; MS (ES+)420.15 (M+H), (ES−)418.17 (M−H); HPLC-Method A, R_(t) 3.07min.

EXAMPLE 62[2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-62)

[0805] Prepared in DMF (37% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.0 (s, 1H), 10.8 (s, 1H), 8.72 (d, 1H), 7.97 (t, 1H), 7.90(d, 1H), 7.75 (t, 1H), 7.53 (m, 3H), 7.43 (t, 1H), 7.35 (d, 1H), 7.23(t, 1H) ppm; LCMS (ES+)424.08 (M+H), (ES−)422.10 (M−H); HPLC-Method A,R_(t) 3.06 min.

EXAMPLE 63 (2-(2-Chloro-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-63)

[0806] Prepared in 91% yield. ¹HNMR (500 MHz, DMSO-d6) δ 7.06 (t, 1H),7.36 (t, 1H), 7.39 (t, 1H), 7.52 (m, 3H), 7.62 (d, 1H), 7.72 (d, 1H),7.82 (m, 1H), 7.90 (d, 1H), 8.05 (m, 1H), 8.76 (d, 1H), 11.5 (m, 1H),13.02 (s, 1H); EI−MS 372.1 (M+1); HPLC-Method A, R_(t) 2.93 min.

EXAMPLE 64(5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yll-amine(II-64)

[0807] Prepared in DMF (57% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.4 (s, br, 1H), 11.4 (br, 1H), 8.72 (d, 1H), 8.12 (s, 1H),7.98 (t, 1H), 7.83 (d, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.60 (m, 4H),7.52 (d, 1H) ppm; LC−MS (ES+)474.12 (M+H), (ES−)472.17 (M−H);HPLC-Method A, Rt 3.25 min.

EXAMPLE 65(4-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-65)

[0808] Prepared in DMF (8% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.7 (s, br, 1H), 11.2 (br, 1H), 8.70 (d, 1H), 8.05 (s, 1H),7.85 (m, 3H), 7.65 (m, 4H), 7.51 (m, 2H) ppm; LC−MS (ES+)474.13 (M+H),(ES−)472.17 (M−H); HPLC-Method A, R_(t) 3.15 min.

EXAMPLE 66[2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-66)

[0809] Prepared in DMF (30% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.69 (d, 1H), 7.95 (t, 1H), 7.82(d, 1H), 7.73 (t, 1H), 7.56 (d, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.39(m, 2H), 7.26 (t, 1H), 6.92 (t, 1H) ppm; LC−MS (ES+) 406.11 (M+H),(ES−)404.12 (M−H); HPLC-Method A, R_(t) 3.00 min.

EXAMPLE 67 (1H-indazol-3-yl)-[2-(2-methyl-phenyl)-quinazolin-4-yl]-amine(II-67)

[0810] Prepared in 55% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.15 (s, 3H),7.09 (t, 1H), 7.26 (d, 1H), 7.31 (t, 1H), 7.39 (t, 1H), 7.42 (m, 1H),7.55 (d 1H), 7.64 (d, 1H), 7.74 (d, 1H), 7.89 (m, 1H), 7.96 (d, 1H),8.10 (m, 1H), 8.81 (d, 1H), 12.0 (m, 1H), 13.18 (s, 1H); EI−MS 352.2(M+1); HPLC-Method A, R_(t) 2.93 min.

EXAMPLE 68(7-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-68)

[0811] Prepared in DMF (75% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.5 (s, br, 1H), 11.2 (s, br, 1H), 8.68 (d, 1H), 7.97 (t,1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.74 (t, 1H), 7.70 (d, 1H), 7.68 (d,1H), 7.64 (m, 2H), 7.57 (m, 1H), 7.14 (t, 1H) ppm; LC−MS (ES+)474.11(M+H), (ES−)472.14 (M−H); HPLC-Method A, R_(t) 3.24 min.

Example 69(6-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-69)

[0812] Prepared by Method B in DMF (78% yield) as yellow solid. ¹HNMR(500 MHz, DMSO-d6) δ 13.4 (s, br, 1H), 11.1 (s, br, 1H), 8.67 (d, 1H),7.95 (t, 1H), 7.82 (m, 3H), 7.72 (m, 2H), 7.63 (m, 2H), 7.57 (t, 1H),7.23 (d, 1H) ppm; LC−MS (ES+)474.12 (M+H), (ES−)472.15 (M−H);HPLC-Method A, R_(t) 3.28 min.

EXAMPLE 70(5-Nitro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-70)

[0813] Prepared in DMF (82% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.6 (s, br, 1H), 11.4 (s, br, 1H), 8.75 (s, 1H), 8.72 (d,1H), 8.09 (dd, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.75 (t, 1H), 7.70 (m,2H), 7.61 (m, 3H) ppm; LC−MS (ES+)451.14 (M+H), (ES−)449.12 (M−H);HPLC-Method A, R_(t) 3.02 min.

EXAMPLE 71(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-71)

[0814] Prepared in DMF (60% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.7 (s, br, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t,1H), 7.88 (d, 1H), 7.80 (m, 2H), 7.70 (m, 3H), 7.32 (m, 2H) ppm; LC−MS(ES+)442.14 (M+H), (ES−)440.14 (M−H); HPLC-Method A, R_(t) 3.11 min.

EXAMPLE 72

[0815](4-Pyrrol-1-yl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-72)

[0816] Prepared in DMF (33% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.4 (s, br, 1H), 11.0 (s, br, 1H), 8.53 (d, 1H), 7.98 (t,1H), 7.75 (m, 4H), 7.62 (m, 2H), 7.52 (d, 1H), 7.43 (t, 1H), 7.05 (d,1H), 6.80 (s, 2H), 5.61 (s, 2H) ppm; LC−MS (ES+)471.18 (M+H),(ES−)469.18 (M-−H); HPLC-Method A, R_(t) 3.12 min.

EXAMPLE 73(5-Amino-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-73)

[0817] A solution of compound II-70 (70 mg, 0.16 mmol) in MeOH (2 mL)was treated with Raney Ni until solution was colorless (about 1.5 gRaney Ni was added). After stirring at room temperature for 40 min, themixture was filtered through celite, the resulting celite was washedwith MeOH (5 times), and the solvent was evaporated in vacuo to providea crude product that was then purified by HPLC to give the titlecompound as a yellow solid (10 mg, 15%). m.p. 221-223° C.; ¹HNMR (500MHz, DMSO-d6) δ 13.2 (s, br, 1H), 10.7 (s, br, 1H), 9.80 (br, 2H), 8.68(d, 1H), 7.97 (t, 1H), 7.87 (d, 1H), 7.75 (m, 2H), 7.65 (m, 5H), 7.30(d, 1H) ppm; MS (ES+)421.16 (M+H), (ES−) 419.17 (M−H); HPLC-Method A,R_(t) 2.41 min.

EXAMPLE 74[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-74):

[0818] Prepared in DMF (35% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) 613.7 (s, 1H), 11.7 (s, br, 1H), 8.80 (d, 1H), 8.15 (t, 1H),7.99 (d, 1H), 7.88 (t, 1H), 7.68 (d, 1H), 7.60 (m, 2H), 7.53 (t, 1H),7.46 (t, 1H), 7.25 (dd, 1H), 7.04 (m, 1H) ppm; LC−MS (ES+)390.16 (M+H);HPLC-Method A, R_(t) 3.00 min.

EXAMPLE 75[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-75)

[0819] Prepared in DMF. ¹HNMR (500 MHz, DMSO-d6) δ 13.2 (s, 1H), 11.7(s, br, 1H), 8.80 (d, 1H), 8.10 (t, 1H), 7.91 (m, 2H), 7.70 (d, 1H),7.58 (m, 4H), 7.50 (t, 1H), 7.29 (t, 1H) ppm; LC−MS (ES+) 390.17 (M+H);HPLC-Method A, R_(t) 3.00 min.

EXAMPLE 76[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-76)

[0820] Prepared in DMF (55% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.8 (s, 1H), 11.5 (s, br, 1H), 8.76 (d, 1H), 8.08 (t, 1H),7.93 (d, 1H), 7.84 (t, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.50 (t, 1H),7.44 (m, 2H), 7.36 (t, 1H) ppm; LC−MS (ES+)408.15 (M+H), (ES−)406.17(M−H); HPLC-Method A, R_(t) 3.08 min.

EXAMPLE 77[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5-trifluoromethyl-1H-indazol-3-yl)-amine(II-77)

[0821] Prepared in DMF (66% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.5 (s, 1H), 11.4 (s, br, 1H), 8.79 (d, 1H), 8.29 (s, 1H),8.07 (t, 1H), 7.93 (d, 1H), 7.84 (t, 1H), 7.72 (d, 1H), 7.63 (d, 2H),7.53 (d, 1H), 7.48 (t, 1H), 7.36 (t, 1H) ppm; LC−MS (ES+): m/e=440.16(M+H); (ES−): m/e=438.18 (M−H); HPLC-Method A, R_(t) 3.22 min.

EXAMPLE 78 [2-(2-cyano-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-78)

[0822] Prepared in 13% yield. ¹H-NMR (500 MHz, DMSO) δ 12.9 (br, 1H),10.8 (br, 1H), 8.73 (br s, 1H), 7.97 (m, 4H), 7.74 (m, 1H), 7.5 (m, 4H),7.42 (m, 1H), 7.08 (m, 1H) ppm; MS (FIA)363.2 (M+H); HPLC-Method A,R_(t) 2.971 min.

EXAMPLE 79(5-Bromo-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-79)

[0823] Prepared in DMF (64% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6)813.4 (s, 1H), 11.6 (s, br, 1H), 8.93 (d, 1H), 8.21 (t, 1H),8.14 (s, 1H), 8.05 (d, 1H), 7.95 (m, 4H), 7.86 (t, 1H), 7.65 (d, 1H),7.59 (d, 1H) ppm; MS (ES+)486.10 (M+H), (ES−)484.09 (M−H); HPLC-MethodA, R_(t) 3.22 min.

EXAMPLE 80(6-Chloro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-80)

[0824] Prepared in DMF (94% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.1 (s, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t, 1H),7.87 (d, 1H), 7.79 (m, 2H), 7.73 (m, 2H), 7.67 (m, 2H), 7.58 (s, 1H),7.04 (dd, 1H) ppm. LC−MS (ES+)440.14 (M+H), (ES−)438.16 (M−H);HPLC-Method A, R_(t) 3.25 min.

EXAMPLE 81(7-Fluoro-6-trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-81)

[0825] Prepared in DMF (30% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.9 (s, 1H), 11.0 (s, br, 1H), 8.64 (d, 1H), 7.94 (t, 1H),7.81 (d, 1H), 7.71 (m, 2H), 7.60 (m, 4H), 7.20 (dd, 1H) ppm. LC−MS(ES+)492.18 (M+H), (ES−)490.18 (M−H); HPLC-Method A, R_(t) 3.44 min.

EXAMPLE 82(6-Bromo-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-82)

[0826] Prepared in DMF (40% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.1 (s, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t, 1H),7.87 (d, 1H), 7.80 (m, 2H), 7.73 (m, 3H), 7.67 (m, 1H), 7.61 (d, 1H),7.15 (dd, 1H) ppm; MS (ES+)486.07 (M+H); HPLC-Method A, R_(t) 3.28 min.

EXAMPLE 83[2-(2,4-Bis-trifluoromethyl-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-83)

[0827] Prepared in DMF in 28% yield. ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d,J=8.4 Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC−MS (ES+)510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

EXAMPLE 84(5,7-Difluoro-1H-indazol-3-yl)-[2-(4-fluoro-2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-84)

[0828] Prepared in 48% yield. ¹HNMR (500 MHz, MeOH-d4)88.74-8.63 (m,1H), 8.23-8.10 (m, 1H), 7.99-7.90 (m, 2H), 7.89-7.80 (m, 1H), 7.71-7.61(m, 1H), 7.61-7.50 (m, 1H), 7.24-7.15 (m, 1H), 7.14-7.02 (m, 1H); LC−MS(ES+)460.14 (M+H); HPLC-Method C, R_(t) 7.59 min.

EXAMPLE 85[2-(2-Bromo-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-85)

[0829] Prepared in THF (21% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d,J=8.4 Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC−MS (ES+) 510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

EXAMPLE 86(5,7-Difluoro-1H-indazol-3-yl)-[2-(5-fluoro-2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-86)

[0830] Prepared in THF (26% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.62 (d,J=8.4 Hz, 1H), 8.16-8.02 (m, 1H), 7.96-7.73 (m, 3H), 7.59-7.48 (m, 1H),7.48-7.35 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 1H); LC−MS(ES+)460.16 (M+H); HPLC-Method C, R_(t) 7.28 min.

EXAMPLE 87 [2-(2,4-Dichloro-phenyl)-quinazolin-4-yl-(5,7-Difluoro-1H-indazol-3-yl)-amine (II-87)

[0831] Prepared in THF (16% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d,J=8.4 Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC−MS (ES+)510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

EXAMPLE 88[2-(2-Chloro-5-trifluoromethyl-phenyl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-88)

[0832] Prepared in THF (33% yield). ¹HNMR (500 MHz, DMSO-d6) δ 10.76 (s,1H), 8.66 (d, J=8.3 Hz, 1H), 8.06-7.84 (m, 3H), 7.81-7.63 (m, 3H),7.48-7.16 (m, 2H); LC−MS (ES+)476.16 (M+H); HPLC-Method C, R_(t) 19.28min.

EXAMPLE 89(4-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-89)

[0833] Prepared in NMP (79% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.2 (s, 1H), 10.8 (s, br, 1H), 8.63 (d, 1H), 7.97 (t, 1H),7.85 (d, 1H), 7.74 (m, 2H), 7.64 (t, 1H), 7.57 (m, 2H), 7.32 (m, 2H),6.82 (m, 1H) ppm; LC−MS (ES+) 424.17 (M+H); HPLC-Method A, R_(t) 3.14min.

EXAMPLE 90(1H-Indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-90)

[0834] Prepared using THF as solvent to afford the title compound as aTFA salt (23% yield). HPLC-Method A, R_(t) 2.97 min (95%); ¹HNMR(DMSO-d6, 500 MHz) δ 12.9 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m),7.75-7.50 (8H, s), 7.30 (1H, m), 6.90 (1H, m), 4.0 (3H, s); MS(m/z)436.2 (M+H).

EXAMPLE 91(5-Fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-91)

[0835] Prepared using TFA as solvent to afford the title compound as aTFA salt (23% yield). HPLC-Method A, R_(t) 3.10 min. (99%); ¹HNMR(DMSO-d6, 500 MHz): 13.0 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m),7.75-7.50 (7H, m), 7.35 (1H, m), 7.25 (1H, m), 4.0 (3H, s); MS(m/z)454.2 (M+H).

EXAMPLE 92(7-Fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-92)

[0836] Prepared using THF as solvent to afford the title compound as aTFA salt (98 mg, 58% yield). HPLC-Method A, R_(t) 3.20 min (92%); ¹HNMR(DMSO-d6, 500 MHz) δ 13.45 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m),7.75-7.60 (5H, m), 7.50 (1H, m), 7.40 (1H, m), 7.15 (1H, m), 6.95 (1H,m)4.0 (3H, s); MS (m/z) 454.2 (M+H).

EXAMPLE 93(5,7-Difluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-93)

[0837] Prepared using THF as solvent to afford the title compound as aTFA salt (36% yield). HPLC-Method A, R_(t) 3.27 min. (95%); ¹HNMR(DMSO-d6, 500 MHz): 13.65 (1H, bs), 11.0-10.7(1H, bs), 8.22 (1H, m),7.75-7.60 (5H, m), 7.40 (1H, m), 7.35 (1H, m), 7.19 (1H, m), 4.0 (3H,s); MS (m/z)472.2 (M+H).

EXAMPLE 94[2-(2-Chloro-pyridin-3-yl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-94)

[0838] Prepared in DMF. ¹HNMR (500 MHz, DMSO-d6) δ 13.62 (br s, 1H,11.06-10.71 (m, 1H), 8.16-7.70 (m, 4H), 7.60-7.09 (m, 3H); LC−MS (ES+)409.14 (M+H); HPLC-Method A, R_(t) 2.89 min.

EXAMPLE 95[2-(2-Chloro-4-nitro-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-95)

[0839] Prepared in THF. ¹HNMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.74(s, 1H), 8.67 (d, J=8.4 Hz, 1H), 8.29 (d, J=2.05 Hz, 1H), 8.18- 8.08 (m,1H), 8.07-7.60 (m, 4H), 7.53-7.10 (M, 2H). LC−MS (ES+) 453.15 (M+H);HPLC-Method D, R_(t) 3.63 min.

EXAMPLE 96[2-(4-Amino-2-chloro-phenyl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-96)

[0840] A solution of compound II-95 (8 mg, 0.018 mmol) and tin chloridedihydrate (22 mg, 0.1 mmol) in ethanol (2 mL) was heated at 100° C. for24 h. The reaction was diluted with EtOAc (10 mL), washed with 1N NaOHsolution (2×10 mL), brine, and dried over anhydrous sodium sulfate toafford the crude product. Purification was achieved by flashchromatography on silica gel (eluting with 1-3% MeOH in CH₂Cl₂.) Thetitle compound was isolated as pale yellow solid (1.2 mg, 16% yield).LC−MS (ES+)423.12 (M+H), HPLC-Method C, R_(t) 13.78 min.

EXAMPLE 97 (4,5,6,7-Tetrahydro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (II-97)

[0841] Prepared in 34% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.58 (m, 2H),1.66 (m, 2H), 2.24 (m, 2H), 2.54 (m 2H), 7.63 (m, 3H), 7.71 (t, 1H),7.75 (d, 1H), 7.78 (d, 1H), 7.85 (t, 1H), 8.53 (d, 1H), 9.99 (s, 1H),12.09 (s, 1H); EI−MS 410.2 (M+1); HPLC-Method A, R_(t) 3.05 min.

EXAMPLE 98(1H-Pyrazolo[4,3-blpyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-98)

[0842] Prepared in DMF (37% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.1 (s, br, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.54 (dd,1H), 8.12 (d, 1H), 8.06 (t, 1H), 7.90 (d, 1H), 7.84 (t, 1H), 7.75 (d,1H), 7.69 (m, 2H), 7.65 (t, 1H), 7.47 (dd, 1H) ppm; LC−MS (ES+)407.18(M+H); HPLC-Method A, R_(t) 2.77 min.

EXAMPLE 99(1H-Pyrazolo[3,4-pyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-99)

[0843] Prepared in DMF (45% yield). ¹HNMR (500 MHz, DMSO-d6) δ 13.5 (s,br, 1H), 11.3 (s, br, 1H), 8.78 (d, 1H), 8.49 (d, 1H), 8.17 (d, 1H),8.03 (t, 1H), 7.89 (d, 1H), 7.80 (m, 2H), 7.74 (m, 2H), 7.68 (m, 1H),7.08 (dd, 1H) ppm. MS (ES+)407.16 (M+H), (ES−) 405.16 (M−H); HPLC-MethodA, R_(t) 2.80 min.

EXAMPLE 100(6-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-100)

[0844] Prepared in DMF (11% yield). ¹HNMR (500 MHz, DMSO-d6) δ 13.2 (s,br, 1H), 10.8 (s, br, 1H), 8.57 (d, 1H), 7.95 (t, 1H), 7.82 (d, 1H),7.72 (t, 1H), 7.65 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H, buried by DMSO),2.20 (s, 3H) ppm. LC−MS (ES+)435.22 (M+H), (ES−)433.25 (M−H);HPLC-Method A, R_(t) 2.94 min.

EXAMPLE 101

[0845](6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amineII-101

[0846] Prepared in DMF (6% yield). ¹HNMR (500 MHz, DMSO-d6) δ 12.6 (s,1H), 11.0 (s, br, 1H), 8.60 (d, 1H), 7.95 (t, 1H), 7.88 (d, 1H), 7.80(d, 1H), 7.68 (m, 4H), 7.40 (s, 3H), 7.22 (s, 2H), 6.61 (s, 1H) ppm.LC−MS (ES+)500.21 (M+H), (ES−) 498.16 (M−H); HPLC-Method A, R_(t) 3.00min.

EXAMPLE 103[6-Methyl-2-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(II-103)

[0847] MS 412.13 (M+H); HPLC-Method E R_(t) 1.248 min.

EXAMPLE 104(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-amine(II-104)

[0848] MS 402.12 (M+H); HPLC-Method E, R_(t) 1.188 min.

EXAMPLE 105[6-Ethyl-2-,(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-105)

[0849] MS 364.14 (M+H); HPLC-Method E, R_(t) 1.112 min.

EXAMPLE 106[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-106)

[0850]¹HNMR (500 MHz, DMSO) δ 12.23 (s, 1H), 10.78 (s, 1H), 7.73-7.47(m, 7H), 6.72 (s, 1H), 2.21 (s, 3H). MS: (M+H)337.02. HPLC-Method A,R_(t) 2.783 min.

EXAMPLE 107(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-107)

[0851] Prepared in 68% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.16 (t, 2H),2.88 (m, 2H), 2.98 (t, 2H), 7.21 (td, 1H), 7.29 (dd, 1H), 7.50 (dd, 1H),7.65 (t, 1H), 7.67 (t, 1H), 7.73 (t, 1H), 7.79 (d, 1H), 10.22 (br. s,1H), 12.99 (br. s, 1H); EI−MS 414.2 (M+H); HPLC-Method A, R_(t) 2.92min.

EXAMPLE 108(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine(II-108)

[0852] HPLC-Method A, R_(t) 2.78 min. (95%); ¹HNMR (DMSO-d6, 500 MHz):12.95 (1H, bs), 11.45 δ 11.15(1H, bs), 9.20 (2H, m), 7.85-7.70 (2H, m),7.70-7.55 (4H, m), 7.50 (1H, m), 7.35 (1H, m), 7.05 (1H, m); MS (m/z)407.03 (M+H).

EXAMPLE 109(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine(II-109)

[0853] Yellow, di-TFA salt (25% yield). HPLC (Method A)3.10 min. (95%);¹HNMR (DMSO-d6, 500 MHz): 13.8-13.6 (1H, bs), 11.4-11.2(1H, bs), 9.15(2H, m), 7.85-7.75 (2H, m), 7.75-7.62 (3H, m), 7.32 (2H, m); MS (m/z)442.98 (M+H).

EXAMPLE 110[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-110)

[0854] Prepared from 2-aminonicotinic acid and 2-chlorobenzoyl chlorideafforded the title compound as a di-TFA salt (28% yield). HPLC-Method A,R_(t) 2.85 min. (95%); ¹HNMR (DMSO-d6, 500 MHz): 12.90 (1H, s),11.10-10.90 (1H, bs), 9.05 (2H, m), 7.75-7.60 (2H, m), 7.51 (1H, m),7.45-7.25 (5H, m), 6.95 (1H, m); MS (m/z) 372.99 (M+H).

EXAMPLE 111(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-111)

[0855] Prepared in 43% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H),1.53 (m, 2H), 1.77 (m, 4H), 2.95 (m, 2H), 3.04 (m, 2H), 7.22 (m, 2H),7.50 (dd, 1H), 7.72 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.05 (br s,1H); EI−MS 456.2 (M+H); HPLC-Method C, R_(t) 11.93 min.

EXAMPLE 112[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-112)

[0856] Prepared in 67% yield. ¹HNMR (500 MHz,. DMSO-d6)82.18 (m, 2H),2.89 (m, 2H), 3.02 (t, 2H), 7.24 (td, 1H), 7.42 (m, 2H), 7.49 (td, 1H),7.52 (dd, 1H), 7.54 (d, 1H), 7.57 (dd, 1H), 10.50 (br. s, 1H), 13.06(br. s, 1H); EI−MS 380.1 (M+1); HPLC-Method C, R_(t) 9.68 min.

EXAMPLE 113(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-113)

[0857] Prepared in 37% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.65 (m, 2H),2.85 (m, 2H), 2.99 (t, 2H), 7.02 (t, 1H), 7.32 (t, 1H), 7.47 (d, 1H),7.55 (d, 1H), 7.68 (t, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 10.37 (br. s,1H), 12.91 (br. S, 1H); EI−MS 396.1 (M+H); HPLC-Method B, R_(t) 9.88min.

EXAMPLE 114(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-114)

[0858] Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.15 (m, 2H),2.87 (m, 2H), 2.97 (t, 2H), 6.99 (td, 1H), 7.17 (dd, 1H), 7.38 (d, 1H),7.65 (m, 2H), 7.71 (t, 1H), 7.78 (d, 1H), 10.21 (br. s, 1H), 13.40 (br.s, 1H); EI−MS 414.1 (M+H); HPLC-Method C, R_(t) 9.99 min.

EXAMPLE 115(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-115)

[0859] Prepared according to Method C in 52% yield. ¹HNMR (500 MHz,DMSO-d6) δ 2.16 (m, 2H), 2.89 (m, 2H), 2.97 (t, 2H), 7.19 (dd, 1H), 7.29(td, 1H), 7.63 (t, 1H), 7.66 (d, 1H), 7.71 (t, 1H), 7.78 (d, 1H), 10.16(br. s, 1H), 13.55 (br. s, 1H); EI−MS 432.1 (M+H); HPLC-Method C, R_(t)10.09 min.

EXAMPLE 116[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-116)

[0860] Prepared in 56% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.16 (m, 2H),2.85 (m, 2H), 3.01 (t, 2H), 7.06 (t, 1H), 7.34 (t, 1H), 7.40 (t, 1H),7.48 (m, 2H), 7.53 (d, 1H), 7.56 (d, 1H), 7.63 (d, 1H), 10.39 (br. s,1H), 12.91 (s, 1H); EI−MS 362.1 (M+H); HPLC-Method A, R_(t) 3.09 min.

EXAMPLE 117[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-117)

[0861] Prepared in 63% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.15 (m, 2H),2.87 (m, 2H), 3.00 (t, 2H), 7.01 (td, 1H), 7.19 (dd, 1H), 7.39 (t, 1H),7.45 (m, 2H), 7.51 (d, 1H), 7.55 (d, 1H), 10.35 (br. s, 1H), 13.45 (br.s, 1H); EI−MS 380.1 (M+H); HPLC-Method A, R_(t) R_(t) 3.15 min.

EXAMPLE 118[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-118)

[0862] Prepared in 60% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.18 (m, 2H),2.91 (m, 2H), 3.01 (t, 2H), 7.32 (t, 1H), 7.33 (td, 1H), 7.41 (t, 1H),7.48 (t, 1H), 7.53 (d, 1H), 7.55 (dd, 1H), 10.35 (br. s, 1H), 13.45 (br.s, 1H); EI−MS 398.1 (M+H); HPLC-Method A, R_(t) R_(t) 3.24 min.

EXAMPLE 119(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-119)

[0863] Prepared in 36% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.47 (m, 2H),1.53 (m, 2H), 1.78 (m, 4H), 2.96 (m, 2H), 3.06 (t, 2H), 7.03 (t, 1H),7.47 (t, 1H), 7.72 (d, 1H), 7.73 (d, 1H), 7.72 (m, 3H), 7.81 (d, 1H),10.52 (m, 1H), 12.97 (br. s, 1H); EI−MS 438.2 (M+1); HPLC-Method A,R_(t) 3.37 min.

EXAMPLE 120(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-120)

[0864] Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H),1.52 (m, 2H), 1.77 (m, 4H), 2.94 (m, 2H), 3.04 (m, 2H), 7.00 (td, 1H),7.17 (dd, 1H), 7.30 (d, 1H), 7.70 (m, 3H), 7.79 (d, 1H), 10.5 (m, 1H),13.49 (br s, 1H); El-MS 456.1 (M+H); HPLC-Method A, R_(t) 3.43 min.

EXAMPLE 121(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-121)

[0865] Prepared in 48% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H),1.52 (m, 2H), 1.77 (m, 4H), 2.95 (m, 2H), 3.03 (m, 2H), 7.14 (d, 1H),7.30 (t, 1H), 7.73 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.62 (br. s,1H); EI−MS 475.1 (M+1); HPLC-Method A, R_(t) 3.52 min.

EXAMPLE 122[6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-122)

[0866] Prepared in 45% yield. ¹HNMR (500 MHz, CDC13) δ 1.30 (2H, m),1.46 (2H, m), 1.65 (2H, m), 1.76 (2H, m), 1.91 (2H, m), 2.61 (1H, br m),7.08 (1H, t, J=7.4 Hz), 7.27 (1H, d, J=8.0 Hz), 7.35 (1H, t, J=7.1 Hz),7.50 (1H, t, J=7.0 Hz), 7.58 (1H, t, J=7.4 Hz), 7.66 (3H, m), 7.72 (1H,d, J=7.8 Hz), 8.0 (1H, br), 9.87 (1H, br) ppm; HPLC-Method D, R_(t) 3.57min; LC−MS 438.17 (M+H)⁺

EXAMPLE 123[6-(2-Fluoro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-123)

[0867] Prepared in 8% yield. ¹HNMR (500 MHz, CDCl₃) δ 7.18 (3H, m), 7.37(1H, m), 7.43 (1H, t, J=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.55 (1H, t,J=7.6 Hz), 7.65 (1H, t, J=7.4 Hz), 7.79 (1H, d, J=7.9 Hz), 7.85 (1H, d,J=7.6 Hz), 8.19 (2H, m), 8.70 (1H, d, J=8.5 Hz) ppm; HPLC-Method D,R_(t) 4.93 min; LC−MS 450.13 (M+H)⁺

EXAMPLE 124(6-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-124)

[0868] Prepared in DMF (87% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.0 (s, 1H), 11.1 (s, br, 1H), 8.66 (d, 1H), 7.95 (t, 1H),7.80 (d, 1H), 7.72 (m, 2H), 7.62 (m, 4H), 7.21 (dd, 1H), 6.84 (td, 1H)ppm. LC−MS (ES+)424.15 (M+H); HPLC-Method A, R_(t) 3.05 min.

EXAMPLE 1253-[2-(2-Trifluoromethyl-phenyl)-quinazolin-4-ylamino]-1H-indazole-5-carboxylicacid methyl ester (II-125)

[0869] To a solution of compound II-79 (100 mg 0.21 mmol) in DMF (2 mL)was added MeOH (1 mL), DIEA (54 uL, 0.31 mmol) and PdCl₂(dppf)(4 mg,0.005 mmol). The flask was flushed with CO three times and then chargedwith a CO balloon. The reaction mixture was heated at 80° C. for 14 hthen poured into water. The resulting precipitate was collected andwashed with water. The crude product was then purified first by flashcolumn (silica gel, 50% ethyl acetate in hexanes) then by preparativeHPLC to to afford II-125 (32%) as yellow solid. ¹HNMR (500 MHz, DMSO-d6)δ 13.3 (s, 1H), 11.3 (s, br, 1H), 8.70 (d, 1H), 8.36 (s, 1H), 7.97 (t,1H), 7.82 (m, 2H), 7.71 (m, 3H), 7.58 (m, 2H), 7.51 (d, 1H), 3.75 (s,3H) ppm; LC−MS (ES+) 464.13 (M+H); HPLC-Method A, R_(t) 3.12 min.

EXAMPLE 208(5-Methyl-2H-pyrazol-3-yl)-[2-(2-naphthyl-1-yl)-quinazolin-4-yl]-amine(II-208)

[0870]¹HNMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.73 (m, 1H), 8.39 (m,1H), 8.09 (m, 2H), 7.95 (m, 3H), 7.62 (m, 3H), 6.78 (s, 1H), 2.32 (s,3H); MS 352.2 (M+H).

EXAMPLE 209[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-214)

[0871] Prepared from4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol)and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification bypreparative HPLC afforded the title compound as a yellow, di-TFA salt(93 mg, 46% yield). HPLC-Method A, R_(t) 3.04 min; ¹H NMR (DMSO, 500MHz): δ 13.67 (1H, s), 11.40-11.25 (1H, bs), 9.35-9.25 (2H, m), 7.95(1H, m), 7.80-7.47 (5H, m), 7.35(1H, m), 7.15 (1H, m); MS (m/z),MH⁺391.1.

EXAMPLE 210[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-215)

[0872] Prepared from4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol)and 5-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification bypreparative HPLC afforded the title compound as a yellow, di-TFA salt(45 mg, 22% yield). HPLC-Method A, R_(t) 3.00 min; ¹H NMR (DMSO, 500MHz): δ 13.0 (1H, s), 10.90(1H, bs), 9.15-9.05 (2H, m), 7.70 (1H, m),7.60-7.30 (6H, m), 7.20 (1H, m); MS (m/z), MH⁺391.1.

EXAMPLE 211[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-216):

[0873] Prepared from4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol)and 7-Difluoro-1H-indazol-3-ylamine (112 mg, 0.66 mmol). Purification bypreparative HPLC afforded the title compound as a yellow, di-TFA salt(130 mg, 62% yield). HPLC-Method A, R_(t) 3.12 min; ¹H NMR (DMSO, 500MHz): 13.80-13.60 (1H, bs), 11.30-11.10 (1H, bs), 9.20-9.10 (2H, m),7.80 (1H, m), 7.60-7.30 (6H, m); MS (m/z), MH⁺409.1.

EXAMPLE 212[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-217)

[0874] Prepared from4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol)and 1H-indazol-3-ylamine (88 mg, 0.66 mmol) Purification by preparativeHPLC afforded the title compound as a yellow, di-TFA salt (72 mg, 33%yield). HPLC-Method A, R_(t) 3.21 min; ¹H NMR (DMSO, 500 MHz): δ 12.95(1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.65(1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00(1H, m); MS (m/z),MH⁺373.1.

EXAMPLE 213[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-218)

[0875] Prepared from4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol)and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification bypreparative HPLC afforded the title compound as a yellow, di-TFA salt(48.7 mg, 22% yield). HPLC-Method A, R_(t) 3.35 min; ¹H NMR (DMSO, 500MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55(1H, m), 7.70-7.35 (5H, m), 7.25(1H, m), 6.95 (1H, m),; MS (m/z),MH⁺391.08.

EXAMPLE 214[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-219)

[0876] Prepared from 4-chloro-2-(2-chloro-5-fluoro-1H-indazol-3-ylamine(108 mg, 0.72 mmol). Purification by preparative HPLC afforded the titlecompound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A,R_(t) 3.27 min; ¹H NMR (DMSO, 500 MHz): δ 13.05 (1H, s), 10.95 (1H, s),9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.60 (1H, m), 7.55 (1H, m),7.50-7.30 (5H, m), 7.25(1H, m); MS (m/z), MH⁺391.1.

EXAMPLE 215[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-220)

[0877] Prepared from4-chloro-2-(2-chloro-7-difluoro-1H-indazol-3-ylamine (112 mg, 0.66 mmol)

[0878] Purification by preparative HPLC afforded the title compound as ayellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A, R_(t) 3.45 min;¹H NMR (DMSO, 500 MHz): δ 13.65 (1H, s), 11.0 (1H, s), 9.25 (1H, s),8.80 (1H, m), 8.50 (1H, m), 7.60 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H,m); MS (m/z), MH⁺409.1.

EXAMPLE 216 6-Fluoro-1H-indazol-3-ylamine (A1)

[0879]¹HNMR (500 MHz, DMSO-d6) δ 11.4 (s, 1H), 7.68 (dd, 1H), 6.95 (dd,1H), 6.75 (td, 1H), 5.45 (s, 2H) ppm; LC−MS (ES+) 152.03 (M+H);HPLC-Method A, R_(t) 2.00 min.

EXAMPLE 217 5-Fluoro-1H-indazol-3-ylamine (A2)

[0880]¹HNMR (500 MHz, DMSO-d6) δ 11.3 (s, 1H), 7.43 (d, 1H), 7.22 (m,1H), 7.08 (m, 1H), 5.29 (s, 2H) ppm; LC−MS (ES+)152.01 (M+H);HPLC-Method A, R_(t) 1.93 min.

EXAMPLE 218 5,7-Difluoro-1H-indazol-3-yl-amine (A3) ¹HNMR (500 MHz,CD₃OD) δ 7.22 (dd, J=2.0, 8.45 Hz, 1H), 7.04-6.87 (m, 1H); LC−MS(ES+)169.95 (M+H); HPLC-Method C, R_(t) 2.94 min EXAMPLE 2197-Fluoro-1H-indazol-3-ylamine (A4)

[0881]¹HNMR (500 MHz, DMSO-d6) δ 11.8 (s, 1H), 7.42 (d, 1H), 6.97 (m,1H), 6.78 (m, 1H), 5.40 (s, 2H) ppm; LCMS (ES+) 152.01 (M+H);HPLC-Method A, R_(t) 2.00 min.

EXAMPLE 220 7-Fluoro-6-trifluoromethyl-1H-indazol-3-ylamine (A5)

[0882]¹H-NMR (500 MHz, DMSO) δ 12.5 (s, 1H), 7.75 (d, 1H), 7.25 (m, 1H),5.85 (m, 1H) ppm; MS (FIA) 220.0 (M+H); HPLC-Method A, R_(t) 2.899 min.

EXAMPLE 221 6-Bromo-1H-indazol-3-ylamine (A6)

[0883]¹H-NMR (500 MHz, DMSO) δ 11.5 (s, 1H), 7.65 (d, 1H), 7.40 (s, 1H),7.00 (d, 1H), 5.45 (br s, 1H) ppm; MS (FIA)213.8 (M+H); HPLC-Method A,R_(t) 2.441 min.

EXAMPLE 222 4-Fluoro-1H-indazol-3-ylamine (A7)

[0884]¹H-NMR (500 MHz, DMSO) δ 11.7 (s, 1H), 7.17 (m, 1H), 7.05 (d, 1H),6.7 (br, 1H), 6.60 (dd, 1H), 5.20 (br s, 2H) ppm; MS (FIA) 152.0 (M+H);Method A, R_(t) 2.256 min.

EXAMPLE 223 5-Bromo-1H-indazol-3-ylamine (A8)

[0885]¹H-NMR (500 MHz, DMSO) δ 11.55 (br s, 1H), 7.95 (s, 1H), 7.30 (d,1H), 7.20 (d, 1H), 5.45 (br s, 2H) ppm; MS (FIA) 213.8 (M+H); Method A,R_(t) 2.451 min.

EXAMPLE 224 5-Nitro-1H-indazol-3-ylamine (A9)

[0886]¹H-NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.20 (d, 1H), 7.45 (d,1H), 6.15 (br s, 1H) ppm; Method A, R_(t) 2.184 min

EXAMPLE 225 4-Pyrrol-1-yl-1H-indazol-3-ylamine (A10)

[0887]¹H-NMR (500 MHz, DMSO) δ 7.20 (s, 2H), 7.00 (s, 2H), 6.75 (m, 1H),6.25 (s, 2H), 4.30 (d, 1H) ppm; Method A, R_(t) 2.625 min.

EXAMPLE 2264-Chloro-5,6-dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B1)

[0888] Prepared to afford a colorless oil in 75% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H) ppm; MS(FIA) 287.0 (M+H); HPLC-Method A, R_(t) 3.891 min.

EXAMPLE 227 4-Chloro-2-(2-chloro-phenyl)-5,6-dimethyl-pyrimidine (B2)

[0889] Prepared to afford a yellow-orange oil in 71% yield. ¹H-NMR (500MHz, CDCl3) δ 7.73 (m, 1H), 7.52 (m, 1H), 7.39 (m, 2H), 2.66 (s, 3H),2.45 (s, 3H) ppm; MS (FIA) 253.0 (M+H); HPLC-Method A, R_(t) R_(t) 4.156min.

EXAMPLE 228 4-Chloro-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidine(B3)

[0890] Prepared to afford a pale yellow oil in 68% yield. ¹H-NMR (500MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.57 (t,J=7.5 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 2.54 (s, 3H) ppm;MS (FIA)273.0 (M+H); HPLC-Method A, R_(t) 3.746 min.

EXAMPLE 2294-Chloro-6-cyclohexyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B4)

[0891] Prepared to afford a yellow oil in 22% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.70 (m, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H),7.19 (s, 1H), 2.65 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5 (m, 2H), 1.3(m, 2H), 1.2 (m, 2H) ppm; MS (FIA) 341.0 (M+H).

EXAMPLE 230 4-Chloro-6-phenyl-2-(2-trifluoromethyl-phenyl)-pyrimidine(B5)

[0892] Prepared to afford a yellow oil in 53% yield. ¹H-NMR (500 MHz,CDCl3) δ 8.08 (dd, J=7.9, 1.6 Hz, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.77 (d,J=7.8 Hz, 1H), 7.67 (s, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.6 Hz,1H), 7.47 (m, 3H) ppm; MS (FIA)335.0 (M+H); HPLC-Method A, R_(t) 4.393min.

EXAMPLE 231 4-Chloro-2-(2,4-dichloro-phenyl)-5,6-dimethyl-pyrimidine(B6)

[0893] Prepared to afford a white solid in 91% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.62 (d, J=8.3 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.27 (dd,J=8.3, 2.0 Hz, 1H), 2.55 (s, 3H), 2.35 (s, 3H) ppm; MS (FIA) 287, 289(M+H); HPLC-Method A, R_(t) 4.140 min.

EXAMPLE 2324-Chloro-6-(2-chloro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidine(B7)

[0894] Prepared to affod a yellow oil in 52% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.75 (m, 3H), 7.65 (m, 2H), 7.53 (m, 1H), 7.44 (m, 1H), 7.36(m, 2H) ppm; MS (FIA) 369.1 (M+H); HPLC-Method A, R_(t) 4.426 min.

EXAMPLE 2334-Chloro-6-(2-fluoro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidine(B8)

[0895] Prepared to afford a yellow oil in 95% yield. ¹H-NMR (500 MHz,CDCl3) δ 8.24 (t, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J=7.7 Hz, 1H),7.76 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H),7.43 (m, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.13 (m, 1H) ppm; MS (FIA) 353.0(M+H).

EXAMPLE 2344-Chloro-6-pyridin-2-yl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B9)

[0896] Prepared to afford a pale yellow solid in 50% yield. ¹H-NMR (500MHz, CDCl3) δ 8.68 (m, 1H), 8.48 (dd, J=7.9, 0.8 Hz, 1H), 8.38 (d, J=2.3Hz, 1H), 7.84 (m, 3H), 7.62 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H),7.38 (m, 1H) ppm; MS (FIA) 336.0 (M+H); HPLC-Method A, R_(t) 4.575 min.

EXAMPLE 2356-Benzyl-4-chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine(B10)

[0897]¹HNMR (500 MHz, CDCl₃) δ 7.70 (d, 1H), 7.62 (d, 1H); 7.55 (t, 1H),7.48 (t, 1H), 7.32 (m, 4H), 7.25 (m, 1H), 3.74 (s, 2H), 3.66 (s, 2H),2.99 (t, 2H), 2.80 (t, 2H) ppm; LCMS (ES+) 404.17 (M+H); HPLC-Method A,R_(t) 3.18 min.

EXAMPLE 2367-Benzyl-4-chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine(B11)

[0898]¹HNMR (500 MHz, CDCl₃) δ 7.69 (d, 1H), 7.60 (d, 1H), 7.54 (t, 1H),7.47 (t, 1H), 7.28 (m, 4H), 7.20 (m, 1H), 3.68 (s, 2H), 3.67 (s, 2H),2.86 (t, 2H), 2.79 (t, 2H) ppm. MS (ES+) 404.18 (M+H); HPLC-Method A,R_(t) 3.12 min.

EXAMPLE 237 4-Chloro-2-(4-fluoro-2-trifluoromethyl-phenyl)-quinazoline(B12)

[0899]¹HNMR (500 MHz, CD₃OD) δ 8.43 (d, J=8.1Hz, 1H), 8.20-8.05 (m, 2H),8.05-7.82 (m, 2H), 7.71-7.51 (m, 2H). LC−MS (ES+)327.09 (M+H).HPLC-Method D, R_(t) 4.56 min.

EXAMPLE 238 4-Chloro-2-(2-chloro-5-trifluoromethyl-phenyl)-quinazoline(B13)

[0900] LC−MS (ES+)342.97 (M+H). HPLC-Method D, R_(t) 4.91 min.

EXAMPLE 239 4-Chloro-2-(2-chloro-4-nitro-phenyl)-quinazoline (B14)

[0901] LC−MS (ES+)319.98 (M+H). HPLC-Method D, R_(t) 4.45 min.

EXAMPLE 240 4-Chloro-2-(2-trifluoromethyl-phenyl)-quinazoline (B15)

[0902] Prepared in 57% yield. White solid. ¹HNMR (500 MHz, DMSO-d6) δ7.79 (t, 1H), 7.86 (t, 1H), 7.94 (m, 3H), 8.15 (dd, 1H), 8.20 (td, 1H),8.37 (m, 1H); EI−MS 308.9 (M).

EXAMPLE 2414-Chloro-2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidine(B16)

[0903] Prepared in 22% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.19 (m, H),3.01 (t, 2H), 3.08 (t, 2H), 7.49 (t, 1H), 7.55 (t, 1H), 7.62 (d, 1H),7.71 (d, 1H). EI−MS 299.0 (M+H).

EXAMPLE 2424-Chloro-2-(2-chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidine(B17)

[0904] Prepared according to Method C in 82% yield to afford a whitesolid. ¹HNMR (500 MHz, CDCl₃) δ 1.67 (m 4H), 1.87 (m 2H), 3.02 (m 4H),7.28 (m, 2H), 7.40 (m, 1H), 7.65 (m, 1H); EI−MS 293.0 (M+1).

EXAMPLE 2434-Chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidine(B18)

[0905] Prepared in 38% yield to afford a brown oil. ¹HNMR (500 MHz,CDCl₃) δ 1.35 (m 2H), 1.41 (m 2H), 1.76 (m 4H), 2.96 (m, 4H), 7.48 (t,1H), 7.56 (t, 1H), 7.66 (d, 1H), 7.70 (d, 1H); EI−MS 341.0 (M+1).

EXAMPLE 244 4-Chloro-8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazoline(B19)

[0906] Prepared from8-methoxy-2-(2-trifluoromethyl-phenyl)-3H-quinazolin-4-one (1.0 g, 3.12mmol), triethylamine hydrochloride (472 mg, 3.43 mmol), and POCl₃.Purification by flash chromatography afforded a white solid (89% yield).HPLC-Method A, R_(t) 4.10 min, (98%), MS (m/z) 258.08 (M+H).

EXAMPLE 245 2-(4-Chloro-quinazolin-2-yl)-benzonitrile (B20)

[0907] Prepared to afford a yellow solid in 1.5% yield. ¹H-NMR (500 MHz,CDCl3) δ 8.47 (d, 1H), 8.24 (d, 1H), 8.16 (d, 1H), 8.07 (impurity), 7.94(t, 1H), 7.92 (impurity), 7.86 (d, 1H), 7.68 (m, 2H), 7.65 (impurity),7.54 (impurity), 7.49 (t, 1H), 4.2 (impurity), 1.05 (impurity) ppm; MS(LC/MS)266.05 (M+H); HPLC-Method A, R_(t) 3.88 min.

EXAMPLE 246 6-Methyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one(D3)

[0908] Prepared to afford a yellow solid in 50% yield. ¹H-NMR (500 MHz,DMSO-d6) δ 12.7 (br s, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 6.3(s, 1H), 2.21 (s, 3H) ppm; MS (FIA) 255.0 (M+H); HPLC-Method A, R_(t)2.578 min.

EXAMPLE 247 6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one(D4)

[0909] Prepared to afford an off-white solid in 54% yield. ¹H-NMR (500MHz, DMSO-d6) δ 12.9 (br s, 1H), 7.9 (m, 4H), 6.3 (s, 1H), 2.5 (m, 1H),1.9 (m, 5H), 1.4 (m, 5H) ppm; MS (FIA) 323.1 (M+H); HPLC-Method A, R_(t)3.842 min.

EXAMPLE 248 2-(2-Chloro-5-trifluoromethyl-phenyl)-3H-quinazoli-4-one(D10)

[0910]¹HNMR (500 MHz, CD₃OD) δ 8.32-8.25 (m, 1H), 8.01 (s, 1H),7.91-7.72 (m, 1H), 7.66-7.55 (m, 1H). LC−MS (ES+)325.01 (M+H).HPLC-Method D, R_(t) 3.29 min.

EXAMPLE 249 2-(4-Fluoro-2-trifluoromethyl-phenyl)-3H-quinazolin-4-one(D14)

[0911]¹HNMR (500 MHz, CD₃OD) δ 8.28 (d, 8.0 Hz, 1H), 7.94-7.84 (m, 1H),7.84-7.77 (m, 1H), 7.76-7.67 (m, 2H), 7.65-7.53 (m, 2H). LC−MS(ES+)309.06 (M+H). HPLC-Method D, R_(t) 2.88 min.

EXAMPLE 250 2-(4-Nitro-2-chloro-phenyl)-3H-quinazolin-4-one (D15)

[0912] LC−MS (ES+) 302.03 (M+H). HPLC-Method D, R_(t) 2.81 min.

EXAMPLE 251 2-(5-Fluoro-2-trifluoromethyl-phenyl)-3H-quinazolin-4-one(D17)

[0913]¹HNMR (500 MHz, CD₃OD) δ 8.28 (d, R_(t) J=8.05 Hz, 1H), 7.96 (dd,J=5.05, 8.55 Hz, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.78-7.69 (m,1H),7.66-7.46 (m, 3H). LC−MS (ES+)309.14 (M+H). HPLC-Method D, R_(t) 2.90min.

EXAMPLE 252 (1H-Indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-1)

[0914] Prepared by Method A in DMF to afford 70 mg (50% yield) as paleyellow solid. ¹H NMR (500 MHz, DMSO-d6) δ 13.1 (s, br, 1H), 8.48 (d,1H), 7.91 (d, 2H), 7.76 (br, 2H), 7.45 (m, 2H), 7.36 (d, 1H), 7.20 (m,4H), 6.86 (t, 1H) ppm. MS (ES+)338.07 (M+H); (ES−) 336.11 (M−H);HPLC-Method A, R_(t) 2.88 min.

EXAMPLE 253(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-amine(III-7)

[0915] Prepared according to Method A. ¹H NMR (500 MHz, DMSO-d6) δ 12.1(s, br, 1H), 8.70 (s, br, 1H), 8.37 (d, J=6.7 Hz, 2H), 7.54 (m, 3H),6.67 (s, 1H), 2.82 (m, 2H), 2.68 (m, 2H), 2.37 (s, 3H), 1.90 (s, br,4H); MS 306.1 (M+H).

EXAMPLE 254(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl)-amine(III-8)

[0916] MS 320.48 (M+H); HPLC-Method E, R_(t) 1.124 min.

EXAMPLE 255(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-9)

[0917] Yellow solid, mp 286-289° C., ¹H NMR (DMSO) δ 2.35 (3H, s), 6.76(1H, s), 7.61 (1H, m), 7.89 (2H, m), 8.32 (2H, d), 8.70 (1H, d), 8.78(2H, d), 10.56 (1H, br s), 12.30 (1H, br s); IR (solid) 1620, 1598,1571, 1554, 1483, 1413, 1370, 1328; MS 303.2 (M+H)⁺

EXAMPLE 256(7-Chloro-2-pyridin-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-28)

[0918]¹H NMR (DMSO-d6) δ 2.35 (3H,s), 6.75 (1H, s), 7.65 (1H, d), 7.93(1H, s), 8.30 (2H, d), 8.73 (1H, d), 8.79 (2H, d), 10.69 (1H, s), 12.33(1H, s); MS m/z 337.2 (M+H)⁺.

EXAMPLE 257(6-Chloro-2-pyridin-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-29)

[0919]¹H NMR (DMSO-d6) δ 2.31 (3H, s), 6.74 (1H,s), 7.89 (1H, s), 8.30(2H, d), 8.80 (2H, d), 8.91 (1H, s), 10.63 (1H, s), 12.29 (1H, s); MS337.2 (M+H)⁺.

EXAMPLE 258(2-Cyclohexyl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (III-30)

[0920]¹H NMR (DMSO) δ 2.35 (3H, s), 1.70 (3H, m), 1.87 (2H, d), 1.99(2H, d), 2.95 (1H, t), 6.72 (1H, s), 7.75 (1H, d), 7.88 (1H, s), 7.96(1H, s), 8.83 (1H, s), 11.95 (1H, s), 12.70 (1H, s); MS 308.4 (M+H)⁺.

EXAMPLE 259 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-31)

[0921] mp 246° C.; ¹H NMR (400 MHz) δ 2.35 (3H, s), 6.70 (1H, br s),7.51-7.57 (4H, m), 7.83-7.84 (2H, d), 8.47-8.50 (2H, d), 8.65 (1H, d),10.4 (1H, s), 12.2 (1H, bs); IR (solid) 3696, 3680, 2972, 2922, 2865; MS302.1 (M+H)+.

EXAMPLE 260[2-(4-Iodophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-32)

[0922]¹H NMR (DMSO-d6) δ 2.34 (3H, s), 6.72 (1H, s), 7.56 (1H, d), 7.84(2H, d), 7.93 (2H, d), 8.23 (2H, d), 8.65 (1H, s), 10.44 (1H, s), 12.24(1H, s); MS 428.5 (M+H)+.

EXAMPLE 261[2-(3,4-Dichlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-33)

[0923] A suspension of 2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1 g,3.43 mmol) in phosphorus oxychloride (4 mL) was stirred at 110° C. for 3hours. The solvent was removed by evaporation and the residue is treatedcarefully with cold aqueous, saturated NaHCO₃. The resulting solid wascollected by filtration and washed with ether to afford4-chloro-2-(3,5-dichloro-phenyl)-quinazoline as a white solid (993 mg,93%). To the above compound (400mg, 1.29 mmol) in THF (30 mL) was added3-amino-5-methyl pyrazole (396 mg, 2.58 mmol) and the resulting mixtureheated at 65° C. overnight. The solvents were evaporated and the residuetriturated with ethyl acetate, filtered, and washed with the minimumamount of ethanol to afford compound III-33 as a white solid (311 mg65%): mp 274° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.69 (1H, s), 7.60 (1H,m), 7.84 (1H, d), 7.96 (2H, d), 8.39 (1H, dd), 8.60 (1H, d), 8.65 (1H,d), 10.51 (1H, s), 12.30 (1H, s); IR (solid)1619, 1600, 1559, 1528,1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M+H)⁺.

EXAMPLE 262[2-(4-Bromophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34)

[0924] mp 262-265° C.; ¹H NMR (DMSO) δ 2.34 (3S, s), 6.73 (1H, s), 7.55(1H, m), 7.74 (2H, d), 7.83 (2H, m), 8.40 (2H, d), 8.65 (1H, d), 10.44(1H, s), 12.25 (1H, s); IR (solid) 1603, 1579, 1546, 1484, 1408, 1365;MS 380.1/382.1 (M+H)+.

EXAMPLE 263[2-(4-Chlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-35)

[0925] mp >300° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.74 (1H, s),7.53-7.62 (3H, m), 7.84 (2H, d), 8.47 (2H, d), 8.65 (1H, d), 10.44 (1H,s), 12.26 (1H, s); IR (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369,1169; MS 336.2 (M+H)+.

EXAMPLE 264[2-(3,5-Dichlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-36)

[0926] mp 228° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.69 (1H, s), 7.96 (1H,d), 8.21 (3H, m), 8.56 (1H, d), 8.60 (2H, d), 10.51 (1H, s), 12.30 (1H,s); IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370.5 (M+H)+.

EXAMPLE 265[2-(4-Cyanophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-37)

[0927] mp 263° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.72 (1H, s), 7.61 (1H,d), 7.88 (2H, s), 8.04 (2H, d), 8.63 (2H, d), 8.67 (1H, s), 10.52 (1H,s), 12.27 (1H, s); IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2(M+H)+.

EXAMPLE 266[2-(3-lodophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-38)

[0928] mp 234-235° C.; ¹H NMR (DMSO) δ 2.35 (3H, s), 6.73 (1H, s), 7.35(1H, m), 7.56 (1H, m), 7.85 (3H, m), 8.47 (1H, m), 8.65 (1H, m), 8.86(1H, s), 10.49 (1H, s), 12.28 (1H, br s); IR (solid) 1560, 1541, 1469,1360; MS 428.1 (M+H)+.

EXAMPLE 267[2-(4-Ethylsulfanylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-39)

[0929] mp 229-231° C.; ¹H NMR (DMSO) δ 1.29 (3H, t), 2.35 (3H, s), 3.07(2H, q), 6.76 (1H, s), 7.43 (2H, d), 7.51 (1H, m), 7.81 (2H, m), 8.41(2H, d), 8.64 (1H, d), 10.38 (1H, s), 12.24 (1H, br s); IR (solid) 1587,1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 (M+H)+.

EXAMPLE 268(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-40)

[0930] mp 218-219° C.; ¹H NMR (DMSO-d6) δ 0.70-0.80(2H, m), 0.90-1.00(2H, m), 6.70 (1H, s), 7.45-7.55 (4H, m), 7.80-7.85 (2H, m), 8.45-8.55(2H, m), 8.65 (1H, d), 10.40 (1H, s), 12.27 (1H, s); IR (solid) 1624,1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, 828,803, 780, 762, 710; MS 328.2 (M+H)⁺.

EXAMPLE 269[2-(4-tert-Butylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-41)

[0931] mp >300° C.; ¹H NMR (DMSO-d6) δ 1.35 (9H, s), 2.34 (3H, s), 6.79(1H, s), 7.55 (3H, d), 7.85 (2H, d), 8.39 (2H, d), 8.62 (1H, d), 10.35(1H, s), 12.22 (1H, s); IR (solid) 1603, 1599, 1577, 1561, 1535, 1481,1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358.3 (M+H)⁺.

EXAMPLE 270[2-(4-Chlorophenyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(III-42)

[0932]¹H NMR (DMSO-d6) δ 0.77 (4H, br m),2.05 (1H, m), 6.59 (1H, s),7.60 (1H, d), 7.85 (2H, d), 7.91 (2H, d), 8.22 (2H, d), 8.65 (1H, s),10.51 (1H,s), 12.33 (1H,s); MS 362.1 (M+H)⁺.

EXAMPLE 271(2-Benzo[1,3]dioxol-5-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-43)

[0933]¹H NMR (DMSO) δ 2.33 (3H, s), 6.13 (2H, s), 6.78 (1H, s), 7.11(1H, d), 7.80 (1H, t), 7.94 (1H, s), 8.09 (3H, m), 8.25 (1H, d), 10.34(1H, s), 12.21 (1H, s); MS 346.5 (M+H)⁺.

EXAMPLE 272[2-(4-Dimethylaminophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-44)

[0934]¹H NMR (DMSO-d6) δ 2.02 (6H, s), 2.39 (3H, s), 6.83 (1H, s), 7.71(1H, d), 7.98 (2H, s), 8.04 (2H, d), 8.33 (2H, d), 8.67 (1H, s), 11.82(1H, s), 12.72 (1H, s); MS 345.3 (M+H)⁺.

EXAMPLE 273[2-(3-Methoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-45)

[0935] mp 226° C.; ¹H NMR (DMSO) δ 2.34 (3H,s), 3.92 (3H, s), 6.72 (1H,s), 7.21 (1H, d), 7.57 (1H, t), 7.79 (1H, t), 8.02 (3H, m), 8.14 (1H,s), 8.79 (1H, d), 10.39 (1H,s), 12.22 (1H, s); IR (solid) 1599, 1572,1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 (M+H)⁺.

EXAMPLE 275(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dichlorophenyl)-quinazolin-4-yl]-amine(III-46)

[0936]¹H NMR (DMSO-d6) δ 0.86 (2H, d), 1.02 (2H, d), 1.69 (1H, m), 6.56(1H, s), 7.57 (1H, d), 7.84 (4H, m), 8.40 (1H, d), 8.58 (1H, s), 8.64(1H, s), 10.53 (1H, s), 12.36 (1H, s); MS 396.0 (M+H)⁺.

EXAMPLE 276(2-Biphenyl-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-47)

[0937] To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34) (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol)in THF:water (1:1, 4 mL) was added Na₂CO₃ (219 mg, 2.06 mmol),triphenylphosphine (9 mg, {fraction (1/15)} mol %) and palladium acetate(1 mg, 1:135 mol %). The resulting mixture was heated at 80° C.overnight, the solvents were evaporated and the residue purified byflash chromatography (gradient of dichloromethane:MeOH) to afford III-21as a yellow solid (99 mg, 51%): ¹H NMR (DMSO) δ 2.37 (3H, s), 6.82 (1H,s), 7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d),10.42 (1H, s), 12.27 (1H, s); MS 378.2 (M+H)⁺.

EXAMPLE 277[2-(4-Ethynylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-48)

[0938] To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34)(114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5mmol) in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol %), Pd(PPh₃)₂Cl₂(4.2 mg, 1:50 mol %) and triethylamine (121 mg, 0.36 mmol). Theresulting mixture was heated at 120° C. overnight and the solventevaporated. The residue was triturated in ethyl acetate and theresulting precipitate collected by filtration. The collected solid wassuspended in THF (3 mL) and TBAF (1M in THF, 1.1 eq) was added. Thereaction mixture was stirred at room temperature for 2 hours and thesolvent evaporated. The residue was purified by flash chromatography(silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68mg, 70%): ¹H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H, s), 6.74 (1H, s), 7.55(1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43(1H, s), 12.24 (1H, s); MS 326.1 (M+H)⁺.

EXAMPLE 278[2-(3-Ethynylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-49)

[0939] mp 204-207° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 4.28 (1H, s), 6.74(1H, s), 7.55-7.63 (3H, m), 7.83-7.87 (2H, m), 8.49 (1H, d), 8.57 (1H,s), 8.65 (1H, d), 10.46 (1H, s), 12.27 (1H, s); IR (solid)1598, 1574,1541, 1489, 1474, 1422, 1365; MS 326.1 (M+H)+.

EXAMPLE 279[2-(3-Methylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-50)

[0940] A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) inPOCl₃ (60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) washeated under reflux for 2 h. The excess POCl₃ was removed in vacuo, theresidue poured into ice, and the resulting precipitate collected byfiltration. The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53%yield) was washed with water and dried under vacuum for next step usewithout further purification. To a solution of the2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150mL) was added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol) and theresulting mixture was stirred at room temperature for 4 hours. Theresulting precipitate was collected by filtration, washed with ethanol,and dried under vacuum to afford 4.0 g (93% yield) of(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which wasused in the next step without further purification. To a solution of the(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2MNa₂CO₃ (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). The flask wasflushed with nitrogen and the catalyst PdCl₂(dppf)(0.011 mmol) added inone portion. The reaction mixture was then heated at 80° C. for 10hours, cooled to room temperature, and poured into water (2 mL). Theresulting precipitate was collected by filtration, washed with water,and purified by HPLC to afford III-50 as a pale yellow solid (61 mg,75%): ¹H NMR (500 MHz, DMSO-d6) δ 12.3 (br s, 1H), 10.4 (br s, 1H), 8.75(d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45(m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H); MS316.1 (M+H).

EXAMPLE 280[2-(3,5-Difluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-51)

[0941]¹H NMR (500 MHz, DMSO-d6) δ 12.3 (br s, 1H), 10.8 (br s, 1H), 8.63(d, 1H), 7.95 (d, 2H), 7.85 (m, 2H), 7.58 (t, 1H), 7.41 (t, 1H), 6.59(s, 1H), 2.27 (s, 3H); MS 338.1 (M+H).

EXAMPLE 281

[0942][2-(3-Chloro-4-fluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-52)

[0943]¹H NMR (500 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.65(d, 1H), 8.50 (d, 1H), 8.36 (m, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 6.62(s, 1H), 2.30 (s, 3H); MS 354.1 (M+H).

EXAMPLE 282(5-Methyl-2H-pyrazol-3-yl)-[2-(3-trifluoromethylphenyl)-quinazolin-4-yl]-amine(III-53)

[0944]¹H NMR (500 MHz, DMSO-d6) δ 12.2 (br, 1H), 10.45(br, 1H), 7.53 (s,1H), 7.43 (d, J=7.2 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.65 (d, J=8.3 Hz,1H), 6.57 (t, J=7.6 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 6.43 (t, J=7.8 Hz,1H), 6.32 (t, J=7.6 Hz, 1H), 5.51 (s, 1H), 2.03 (s, 3H); MS 370.2 (M+H).

EXAMPLE 283[2-(3-Cyanophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-54)

[0945]¹H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.96 (m, 2H), 8.28 (d,J=7.3 Hz, 1H), 8.16 (s, br, 2H), 8.06 (t, J=7.8 Hz, 1H), 7.88 (m, 1H),6.96 (S, 1H), 2.58 (s, 3H); MS 327.1 (M+H).

EXAMPLE 284[2-(3-Isopropylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-55)

[0946]¹H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=7.5 Hz, 1H), 8.37 (s, 1H),8.26 (s, 1H), 8.08 (m, 2H), 7.81 (t, br, 1H), 7.67 (m, 2H), 6.88 (s,1H), 3.12 (m, 1H), 2.40 (s, 3H), 1.38 (d, J=6.9 Hz, 6H); MS 344.2 (M+H).

EXAMPLE 285(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-3-yl-quinazolin-4-yl)-amine(III-56)

[0947]¹H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.84 (d, J=7.3 Hz, 1H),8.80 (d, J=4.4 Hz, 1H), 8.66 (d, J=8.2 Hz, 1H), 7.87 (m, 2H), 7.77 (m,1H), 7.60 (t, J=7.2 Hz, 1H), 6.67 (s, 1H), 2.28 (s, 3H); MS 303.1 (M+H).

EXAMPLE 286[2-(3-Acetylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-57)

[0948]¹H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.55 (d, J=7.7 Hz, 1H),8.42 (d, J=7.6 Hz, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.76 (m, 2H), 7.58 (t,J=7.7 Hz, 1H), 7.48 (s, br, 1H), 6.60 (s, 1H), 2.49 (s, 3H), 2.03 (s,3H); MS 344.1 (M+H).

EXAMPLE 287

[0949][2-(3,5-Ditrifluoromethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-58)

[0950]¹H NMR (500 MHz, DMSO-d6) δ 10.7 (s, br, 1H), 8.95 (s, 2H), 8.63(d, J=8.2 Hz, 1H), 8.25 (s, 1H), 7.86 (m, 2H), 7.58 (t, J=6.9 Hz, 1H),6.62 (s, 1H), 2.26 (s, 3H); MS 438.1 (M+H).

EXAMPLE 288[2-(3-Hydroxymethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-59)

[0951]¹H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J=7.9 Hz, 1H), 8.33 (s, 1H),8.17 (s, br, 1H), 7.95 (s, br, 1H), 7.89 (s, br, 1H), 7.62 (m, 3H), 6.72(s, 1H), 5.53 (s, 1H), 4.60 (s, 2H), 2.28 (s, 3H); MS 332.1 (M+H).

EXAMPLE 289(5-Methyl-2H-pyrazol-3-yl)-[2-(3-phenoxyphenyl)-quinazolin-4-yl]-amine(III-60)

[0952] mp 231-232° C.; ¹H NMR (DMSO-d6) δ 2.21 (3H, s), 6.59 (1H, s),7.10-7.22 (4H, m), 7.41-7.45 (2H, m), 7.54-7.59 (2H, m), 7.81 (2H, s),8.09 (1H, s), 8.27 (1H, m), 8.64 (1H, m), 10.40 (1H, s), 12.20 (1H, s);IR (solid); IR (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS394.7 (M+H)⁺.

EXAMPLE 290(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-phenoxyphenyl)-quinazolin-4-yl]-amine(III-61)

[0953] mp 193-195° C.; ¹H NMR (DMSO-d6) δ 0.67 (2H, m), 0.93 (2H, m),1.87 (1H,m), 6.56 (1H, s), 7.06-7.20 (4H, m), 7.40-7.43 (2H, m),7.55-7.59 (2H, m), 7.81 (2H, s), 8.11 (1H, s), 8.27 (1H, m), 8.63 (1H,m), 10.43 (1H, s), 12.26 (1H, s); IR (solid); IR (solid) 1589, 1574,1527, 1483, 1369, 1226; MS 420.7 (M+H)⁺.

EXAMPLE 291(5-Methyl-2H-pyrazol-3-yl)-(2-thiophen-3-yl-quinazolin-4-yl)-amine(III-62)

[0954]¹H NMR (500 MHz, DMSO-d6) δ 11.78 (s, br, 1H), 8.75 (d, J=8.1 Hz,1H), 8.68 (s, 1H), 7.98 (dd, J=7.9, 7.5 Hz, 1H), 7.89 (m, 2H), 7.81 (m,1H), 7.68 (t, J=7.5 Hz, 1H), 6.69 (s, 1H), 2.30 (s, 3H); MS 308.1 (M+H).

EXAMPLE 292 (2-Phenyl-quinazolin-4-yl)-(2H-pyrazol-3-yl)-amine (III-63)

[0955] mp 247-249° C.; ¹H NMR (DMSO) δ 6.99 (1H, br s), 7.49-7.58 (5H,m), 7.81 (1H, br s), 7.83 (2H, m), 8.47-8.49 (2H, m), 8.66 (1H, d),10.54 (1H, s), 12.59 (1H, s); IR (solid)3145, 2922, 1622, 1597; MS 288.2(M+H)⁺.

EXAMPLE 293 (2H-Pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-64)

[0956] mp 285-286° C.; ¹H NMR (DMSO) δ 6.99 (1H, br s), 7.65 (1H, m),7.81-7.94 (3H, m), 8.3-8.35 (2H, m), 8.73 (1H, d), 8.84-8.90 (2H, m),10.76 (1H, s), 12.6 (1H, s); IR (solid) 3180, 2972, 1600, 1574; MS 289.2(M+H)⁺.

EXAMPLE 294 5-Ethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-65)

[0957] mp 221-222° C.; ¹H NMR (DMSO) δ 1.31 (3H, t), 2.68 (2H, d), 6.80(1H, s), 7.50-7.60 (4H, m), 8.45-8.55 (2H, m), 8.65-8.75 (1H, m), 10.44(1H,s), 12.27 (1H,s); IR (solid)3190, 1622, 1595, 1575, 1533, 1482,1441, 1420, 1403, 1361, 758, 711; MS 316.2 (M+H)⁺.

EXAMPLE 295 (2-Phenyl-quinazolin-4-yl)-(5-propyl-2H-pyrazol-3-yl)-amine(III-66)

[0958] mp 204-205° C.; ¹H NMR (DMSO-d6) δ 1.02 (3H, t), 1.66-1.75 (2H,m), 2.69 (2H, t), 6.80 (1H, s), 7.45-7.60 (4H,m), 7.80-7.88 (2H, m),8.45-8.50 (2H, m), 8.65 (1H, d), 10.39 (1H, s), 12.25 (1H, s); IR(solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827,808, 763, 709, 697; MS 330.2 (M+H)⁺.

EXAMPLE 296(5-Isopropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-67)

[0959] mp 218-219° C.; ¹H NMR (DMSO-d6) δ 1.36 (6H, d), 3.05 (1H, m),6.86 (1H, s), 7.48-7.59 (4H, m), 7.80-7.88 (2H, m), 8.49-8.58 (2H, m),8.66 (1H, d), 10.47 (1H, s), 12.30 (1H, s); IR (solid) 3173, 2968, 1619,1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798,761, 707, 666, 659; MS 330.2 (M+H)⁺.

EXAMPLE 297(5-tert-Butyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-68)

[0960] mp 136-137° C.; ¹H NMR (DMSO-d6) δ 1.38 (9H, s), 6.87 (1H, br s),7.51-7.57 (4H, m), 7.84-7.85 (2H, m), 8.49-8.51 (2H, m), 8.65 (1H, d),10.43 (1H, s), 12.21 (1H, br s); IR (solid) 3162, 2963, 1621, 1590,1572; MS 344.2(M+H)⁺.

EXAMPLE 298(5-tert-Butyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-69)

[0961] mp >300° C.; ¹H NMR (DMSO) δ 1.38 (9H, s), 6.82 (1H, br s), 7.63(1H, m), 7.86-7.91 (2H, m), 8.32-8.33 (2H, d), 8.69 (1H, d), 8.75-8.76(2H, d), 10.60 (1H, s), 12.31 (1H, br s); IR (solid) 3683, 3149, 2963,1621; MS 345.2(M+H)⁺.

EXAMPLE 299(5-Cyclopentyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-70)

[0962] mp 240-241° C.; ¹H NMR (DMSO-d6) δ 1.68-1.89 (6H, m), 2.03-2.17(2H, m), 3.14-3.22 (1H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.89(2H, m), 8.45-8.52 (2H, m), 8.67 (1H, d), 10.52 (1H, s), 12.26 (1H, s);IR (solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325,999, 951, 801, 775, 761, 747, 710695, 668, 654; MS 356.2(M+H)+.

EXAMPLE 300 (5-Phenyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-71)

[0963] mp 207-209° C.; ¹H NMR (DMSO) δ 7.38-7.40 (1H, m), 7.50-7.58 (6H,m), 7.82-7.88 (4H, m), 8.51 (2H, m), 8.67 (1H, s), 10.58 (1H, s), 13.11(1H, br s); IR (solid) 3345, 3108, 1627, 1612; MS 364.2 (M+H)⁺.

EXAMPLE 301 (5-Carboxy-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-72)

[0964](5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73) (345 mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0mL), stirred at 50° C. for 5 hours, cooled to room temperature, andneutralised with 1M HCl. The mixture was concentrated in vacuo to removeTHF then diluted with water and the resulting precipitate filtered. Theresidual solid was dried at 80° C. under vacuum to afford III-72 as anoff-white solid (312 mg, 94%): mp 289-291° C. (dec.); ¹H NMR (DMSO) δ7.45 (1H, br s), 7.50-7.60 (5H, m), 7.80-7.88 (2H, m), 7.40-7.50 (2H,m), 8.60-8.70 (1H, d), 10.70 (1H, s), 13.00-13.80 (2H, br s); IR (solid)1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004,827, 764, 705; MS 332.3(M+H)⁺.

EXAMPLE 302(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73)

[0965] mp 271-273° C.; ¹H NMR (DMSO) δ 3.95 (3H, s), 7.50-7.65 (5H, m),7.80-7.98 (2H, m), 8.40-8.50 (2H, m), 8.65-8.73 (1H, m), 10.80 (1H, s),13.80 (1H, s); IR (solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500,1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944,827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H)⁺.

EXAMPLE 303(5-Hydroxymethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-74)

[0966] A solution of(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73)(345 mg, Immol) in anhydrous THF (10 mL) was treated withlithium borohydride (125 mg, 5.75 mmol) at 65° C. for 5 hours. Themixture was cooled to room temperature then combined with 2M HCl andethyl acetate. Solid sodium hydrogen carbonate was added to achieve pH 8and the resulting mixture extracted with ethyl acetate. The extractswere dried over magnesium sulphate and concentrated. Purification byflash chromatography (SiO₂, methanol-dichloromethane gradient) affordedIII-74 (95 mg, 30%) as an off-white solid: mp 238-239° C.; ¹H NMR(DMSO)8 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, s), 7.50-7.60(4H, m), 7.85-7.90 (2H, m), 8.48-8.54 (2H, m), 8.69 (1H, 1H), 10.40 (1H,s), 12.48 (1H, s); IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532,1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780,7124; MS 318.2(M+H)⁺.

EXAMPLE 304(5-Methoxymethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-75)

[0967] mp 190-191° C.; ¹H NMR (DMSO) δ 3.34 (3H, s), 4.45 (2H, s), 7.00(1H, s), 7.50-7.62 (4H, m), 7.82-7.90 (2H, m), 8.45-8.52 (2H, m), 8.65(1H, br s), 10.50 (1H, s), 12.30 (1H, s); IR (solid) 3177, 1606, 1589,1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834,813, 766, 707, 691; MS 332.3(M+H)⁺.

EXAMPLE 305[5-(3-Hydroxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-76)

[0968] A solution of(5-benzyloxypropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-78)(20Omg, 0.46 mmol) in toluene (4 mL) and acetonitrile (8 mL) wasstirred with trimethylsilyl iodide (0.64 ml, 4.6 mmol) at 55° C. for 3hours to afford an amber coloured solution. This mixture was dilutedwith ethyl acetate and aqueous sodium hydrogen carbonate. The resultinglayers were separated, the organic layer was dried over magnesiumsulphate and concentrated in vacuo. Purification by flash chromatography(SiO₂, methanol-dichloromethane gradient) affords a yellow oil (115 mg).Trituration with dichloromethane affords III-76 as an off-white soliddried at 75° C. under vacuum (83 mg, 52%): mp 164-165° C.; ¹H NMR (DMSO)δ 1.80-1.90 (2H, m), 2.70-2.80 (2H, m), 3.50-3.60 (2H, m), 4.59 (1H, s),6.80 (1H, s), 7.50-7.60 (4H, m), 7.82-7.90 (2H, m), 8.48-8.53 (2H, m),8.63 (1H, s), 10.40 (1H, s), 12.25 (1H, s); IR (solid) 1622, 1587, 1574,1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952,833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H)⁺.

EXAMPLE 306[5-(3-Methoxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-77)

[0969] mp 169-170° C.; ¹H NMR (DMSO-d6) δ 1.86-1.97 (2H, m), 2.75 (2H,t), 3.30 (3H, s), 3.45 (2H, t), 6.80 (1H, s), 7.50-7.60 (4H, m),7.80-7.90 (2H, m), 8.45-8.55 (2H, m), 8.67 (1H, d), 10.30 (1H, s), 12.25(1H, s); IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373,1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H)⁺.

EXAMPLE 307[5-(3-Benzyloxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-78):

[0970] mp 177-178° C.; ¹H NMR (DMSO) δ 1.92-2.03 (2H, m), 3.76-3.85 (2H,m), 3.52-3.62 (2H, m), 4.51 (2H, s), 6.82 (1H, s), 7.28-7.40 (5H, m),7.46-7.58 (4H, m), 7.80-7.85 (2H, m), 8.47-8.52 (2H, m), 8.66 (1H, d),10.45 (1H, s); IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426,1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H)⁺.

EXAMPLE 308[5-(3-Aminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-79)

[0971] A solution of[5-(3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(II-80)(250 mg, 0.56 mmol), in dichloromethane (3 mL) at 0° C. wastreated with TFA (2 mL). The mixture was warmed to room temperature thenconcentrated in vacuo. The residue was triturated and concentrated fromdichloromethane (3×5 mL) and ether, then triturated with dichloromethaneto crystallize the TFA salt. The resulting solid was collected byfiltration and dissolved in a mixture of ethanol (3 mL ) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then themixture allowed to crystallize. The product was collected by filtrationand dried at 80° C. under vacuum to afford III-79 as an off-white powder(122 mg, 63%): mp 205-207° C.; ¹H NMR (DMSO) δ 1.68-1.83 (2H, m),2.65-2.80(4H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H, m),8.45-8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid)1621, 1598,1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705,677; MS 345.3(M+H)⁺.

EXAMPLE 309[5-(3-tert-Butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-80)

[0972] mp 199-200° C.; ¹H NMR (DMSO) δ 1.37 (9H, s), 1.71-1.82 (2H,m),2.67 (2H, t), 3.00-3.11 (2H, m), 7.81 (1H, s), 7.99 (1H, s), 7.50-7.60(4H, m), 7.80-7.85 (2H, m), 8.48-8.52 (2H, m), 8.63 (1H, d), 10.40 (1H,s), 12.26 (1H, m); IR (solid)2953, 1687, 1622, 1594, 1573, 1535, 1481,1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848,807, 768, 740, 728, 710,693; MS 445.3 (M+H)⁺.

EXAMPLE 3105-Isopropylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-81)

[0973]¹H NMR (500 MHz, DMSO-d6) δ 1.20 (d, J=6.6 Hz, 6H), 4.13 (m, 1H),7.42 (br. s, 1H), 7.61 (dd, J 7.0, 7.7 Hz, 2H), 7.66 (t, J=7.1 Hz, 1H),7.71 (m, 1H), 7.99 (m, 2H), 8.39 (m, 1H), 8.42 (d, J=7.1 Hz, 2H), 8.74(d, J=8.2 Hz, 1H), 11.41 (br. s, 1H); EI−MS 373.2 (M+H); HPLC-Method C,R_(t) 14.09 min.

EXAMPLE 311(5-Allylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-82)

[0974]¹H NMR (500 MHz, DMSO-d6) δ 4.02 (m, 2H), 5.15 (m, 1H), 5.23 (m,1H), 5.94 (m, 1H), 7.45 (br. s, 1H), 7.60 (t, J=6.9 Hz, 2H), 7.64 (m,1H), 7.72 (m, 1H), 7.98 (m, 2H), 8.43 (m 2H), 8.72 (d, J=8.2 Hz, 1H),8.84 (br. s, 1H), 11.34 (br. s, 1H); EI−MS 371.2 (M+H); HPLC-Method C,R_(t) 13.67 min.

EXAMPLE 312[5-(2-Methoxyethylcarbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-83)

[0975]¹H NMR (500 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.48 (m, 4H), 7.36 (br.s, 1H), 7.62 (m, 2H), 7.63 (m, 1H), 7.71 (m, 1H), 7.98 .(m, 2H), 8.41(dd, J=1.4, 7.0, 2H), 8.70 (m, 2H), 11.30 (br. s, 1H); EI−MS 389.2(M+H); HPLC-Method C, R_(t) 12.37 min.

EXAMPLE 313

[0976](5-Benzylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-84): ¹H NMR (500 MHz, DMSO-d6) δ 4.52 (d, J=6.0 Hz, 2H), 7.29 (m,1H), 7.38 (d, J=4.2 Hz, 4H), 7.58 (t, J=7.5 Hz, 2H), 7.63 (m, 1H), 7.72(m, 1H), 7.98 (m, 2H), 8.43 (d, J=7.7 Hz, 2H), 8.72 (d, J=7.5 Hz, 1H),9.23 (br. s, 2H), 11.34 (br. s, 1H); EI−MS 421.2 (M+H); HPLC-Method C,R_(t) 16.76 min.

EXAMPLE 314(5-Cyclohexylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-85)

[0977]¹H NMR (500 MHz, DMSO-d6) δ 1.16 (m, 1H), 1.34 (m, 4H), 1.62 (d,J=2.6 Hz, 1H), 1.76 (m, 2H), 1.85 (m, 2H), 3.79 (m, 1H), 7.43 (m, 1H),7.60 (t, J=7.2 Hz, 2H), 7.65 (t, J=7.1 Hz, 1H), 7.71 (ddd, J=2.2, 5.4,8.2 Hz, 1H), 7.98 (m, 2H), 8.35 (m, 1H), 8.43 (dd, J=1.4, 7.2 Hz, 2H),8.72 (d, J=8.2 Hz, 1H), 11.34 (br. s, 1H); EI−MS 413.5 (M+H);HPLC-Method C, R_(t) 17.18 min.

EXAMPLE 315(5-Diethylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-86)

[0978]¹H NMR (500 MHz, DMSO-d6) δ 1.18 (br. s, 3H), 1.25 (br. s, 3H),3.49 (br. s, 2H), 3.69 (b. s, 2H), 7.21 (s, 1H), 7.59 (t, J=6.9 Hz, 2H),7.62 (m, 1H), 7.70 (m, 1H), 7.96 (m, 2H), 8.39 (d, J=7.1 Hz, 2H), 8.74(d, J=8.4 Hz, 1H), 11.37 (br. s, 1H); EI−MS 387.2 (M+H); HPLC-Method C,R_(t) 14.50 min.

EXAMPLE 316[5-(Benzyl-methyl-carbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-87)

[0979]¹H NMR (500 MHz, DMSO-d6) δ 3.33 (s, 3H), 4.75 (s, 2H), 7.26 (m,1H), 7.31 (m, 1H), 7.38 (m, 4H), 7.58 (m, 2H), 7.70 (m, 1H), 7.95 (m,3H), 8.26 (m, 1H), 8.40 (d, J=7.8 Hz, 2H), 8.75 (m, 1H), 11.2 (br. s,1H); EI−MS 435.2 (M+H); HPLC-Method C, R_(t) 16.77 min.

EXAMPLE 317(2-Phenyl-quinazolin-4-yl)-(5-propylcarbamoyl-2H-pyrazol-3-yl)-amine(III-88)

[0980]¹H NMR (500 MHz, DMSO-d6) δ 0.94 (t, J=7.3 Hz, 3H), 1.57 (m, 2H),3.24 (q, J=6.5 Hz, 2H), 7.39 (br. s, 1H), 7.60 (t, J=7.3 Hz, 2H), 7.64(m, 1H), 7.71 (br. t, J=6.5 Hz, 1H), 7.98 (m, 2H), 8.42 (d, J=7.2 Hz,2H), 8.61 (br. s, 1H), 8.72 (d, J=8.5 Hz, 1H), 11.34 (br. s, 1H); EI−MS373.3 (M+H); HPLC-Method C, R_(t) 13.51 min.

EXAMPLE 318[5-(Ethyl-isopropyl-carbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-89)

[0981]¹H NMR (500 MHz, DMSO-d6) δ 0.92 (t, J=7.4 Hz, 6H), 1.52 (m, 2H),1.59 (m, 1H), 3.79 (m, 2H), 7.53 (br. s, 1H), 7.57 (t, J=7.5 Hz, 2H),7.65 (t, J=7.2 Hz, 1H), 7.71 (m, 1H), 7.99 (m, 2H), 8.23 (br. d, J=8.8Hz, 1H), 8.46 (d, J=7.5 Hz, 2H), 8.74 (d, J=8.4 Hz, 1H), 11.34 (br. s,1H); EI−MS 401.2 (M+H); HPLC-Method C, R_(t) 15.51 min.

EXAMPLE 319(5-Cyclopropylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-90): ¹H NMR (500 MHz, DMSO-d6) δ 0.60 (m, 2H), 0.74 (m, 2H), 2.86(m, 1H), 7.34 (br. s, 1H), 7.62 (m, 3H), 7.70 (m, 1H), 7.97 (m, 2H),8.41 (d, J=7.9 Hz, 2H), 8.63 (br. s, 1H), 8.72 (d, J=7.8 Hz, 1H), 11.35(br. s, 1H); EI−MS 371.2 (M+H); HPLC-Method C, R_(t) 12.64 min. EXAMPLE320(5-Isobutylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-91)

[0982]¹H NMR (500 MHz, DMSO-d6) δ 0.94 (d, J=6.7 Hz, 6H), 1.88 (m, 1H),3.12 (t, J=6.4 Hz, 2H), 7.45 (br. s, 1H), 7.58 (t, J=7.2 Hz, 3H), 7.64(t, J=7.1 Hz, 1H), 7.71 (m, 1H), 7.98 (m, 2H), 8.44 (dd, J=1.3, 7.9 Hz,2H), 8.62 (br. s, 1H), 8.72 (d, J=8.3 Hz, 1H), 11.33 (br. s, 1H); EI−MS387.2 (M+H); HPLC-Method C, R_(t) 14.70 min.

EXAMPLE 321{5-[(3S)-3-Methoxymethyl-pyrrolidine-1-carbonyl]-2H-pyrazol-3-yl}-(2-phenyl-quinazolin-4-yl)-amine(III-93)

[0983]¹H NMR (500 MHz, DMSO-d6) δ 2.00 (m, 2H), 2.12 (m, 1H), 3.29 (s,3H), 3.45 (t, J=8.7 Hz, 1H), 3.57 (dd, J=3.2, 9.3 Hz, 1H), 3.86 (m, 1H),3.92 (m, 1H), 4.36 (m, 2H), 7.45 (br. s, 1H), 7.59 (t, J=7.2 Hz, 2H),7.63 (m, 1H), 7.69 (m, 1H), 7.97 (m, 2H), 8.40 (d, J=7.5 Hz, 2H), 8.74(d, J=7.6 Hz, 1H), 11.38 (br. s, 1H); EI−MS 429.2 (M+H); HPLC-Method C,R_(t) 13.84 min.

EXAMPLE 322(2-Phenyl-quinazolin-4-yl)-(5-m-tolylcarbamoyl-2H-pyrazol-3-yl)-amine(III-94)

[0984]¹H NMR (500 MHz, DMSO-d6) δ 2.33 (s, 3H), 6.97 (d, J=7.5 Hz, 1H),7.27 (t, J=7.8 Hz, 1H), 7.62 (m, 7H), 7.72 (m, 1H), 7.98 (m, 2H), 8.46(dd, J=2.0, 7.9 Hz, 2H), 8.71 (m, 1H), 10.29 (s, 1H), 11.31 (br. s, 1H);EI−MS 421.2 (M+H); HPLC-Method C, R_(t) 17.11 min.

EXAMPLE 323(2-Phenyl-quinazolin-4-yl)-(5-p-tolylcarbamoyl-2H-pyrazol-3-yl)-amine(III-95)

[0985]¹H NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H), 7.20 (d, J=8.3 Hz, 2H),7.62 (m, 5H), 7.68 (d, J=8.3 Hz, 2H), 7.72 (m, 1H), 7.98 (m, 2H), 8.46(dd, J=1.8, 7.0 Hz, 2H), 8.72 (m, 1H), 10.31 (s, 1H), 11.36 (br. s, 1H);EI−MS 421.2 (M+H); HPLC-Method C, R_(t) 16.95 min.

EXAMPLE 324(5-Methylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-96)

[0986]¹H NMR (500 MHz, DMSO-d6) δ 2.82 (d, J=4.6 Hz, 3H), 7.31 (br. s,1H), 7.62 (m, 3H), 7.69 (m, 1H), 7.97 (m, 2H), 8.42 (d, J=7.1 Hz, 2H),8.59 (br. s, 1H), 8.71 (d, J=8.0 Hz, 1H), 11.30 (br. s, 1H); EI−MS 345.1(M+H); HPLC-Method C, R_(t) 11.02 min.

EXAMPLE 325[5-(Morpholine-4-carbonyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-97)

[0987]¹H NMR (500 MHz, DMSO-d6) δ 3.33 (m, 4H), 3.83 (m 4H), 7.34 (br.s, 1H), 7.53 (m, 4H), 7.86 (m, 2H), 8.43 (m, 2H), 8.67 (d, J=8.6 Hz,1H), 10.70 (s, 1H), 13.56 (s, 1H); EI−MS 401.2 (M+H); HPLC-Method A,R_(t) 2.68 min.

EXAMPLE 326[5-(1-Methylpiperazine-4-carbonyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-98)

[0988]1H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.43 (1 m, 4H), 3.87 (m4H), 7.33 (br. s, 1H), 7.53 (m, 4H), 7.87 (m, 2H), 8.45 (m, 2H), 8.67(d, J=7.6 Hz, 1H), 10.70 (s, 1H), 13.30 (s, 1H); EI−MS 414.2 (M+H);HPLC-Method A, R_(t) 2.38 min.

EXAMPLE 327[5-(2-Hydroxyethylcarbamoyl-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-99)

[0989]¹H NMR (500 MHz, DMSO-d6) δ 3.36 (m, 2H), 3.52 (m, 2H), 4.79 (m,1H), 7.50 (m, 5H), 7.83 (m, 2H), 8.50 (m, 4H), 10.52 (br. s, 1H), 13.25(s, 1H); EI−MS 375.1 (M+H); HPLC-Method A, R_(t) 2.51 min.

EXAMPLE 328(5-Carbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-100)

[0990] To a solution of5-(2-phenyl-quinazolin-4-ylamino)-1H-pyrazole-3-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol) in DMF (20 ml) wasadded a solution of ammonia in 1,4-dioxane (0.5 M, 10 ml). The resultingmixture was stirred at room temperature for 24 h. After concentration ofthe solvents, the residue was added to water (20 ml). The resultingprecipitate was collected to afford 111-100 (168 mg, 80%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d6) δ 7.77-7.51 (m, 6H), 7.86 (br s, 2H),8.11 (m, 1H), 8.50 (m, 2H), 8.63 (m, 1H), 10.52 (s, 1H), 11.25 (s, 1H);EI−MS 331.1 (M+H); HPLC-Method A, R_(t) 2.52 min.

EXAMPLE 329 (4-Bromo-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-101)

[0991] Prepared according to Method A to afford a yellow solid, mp 189°C.; ¹H NMR (DMSO-d6) δ 7.44-7.46 (3H, m), 7.58 (1H, m), 7.87 (2H, d),8.15 (1H, s), 8.31-8.34 (2H, m), 8.49 (1H, d), 10.08 (1H, s), 13.13 (1H,s); IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H)⁺.

EXAMPLE 330

[0992](4-Bromo-5-methyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-102)

[0993] mp 183-185° C.; ¹H NMR (DMSO) δ 2.33 (3H, br s), 7.44-7.46 (3H,m), 7.57 (1H, m), 7.84-7.87 (2H, m), 8.31-8.34 (2H, m), 8.48 (1H, d),10.05 (1H, s), 12.91 (1H, br s); IR (solid) 3362, 3065, 2831, 1619,1578; MS 380.2/382.2(M+H)⁺.

EXAMPLE 331 (4-Cyano-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-103)

[0994] mp >250° C.; ¹H NMR (DMSO) δ 7.47-7.49 (3H, m), 7.64 (1H, m),7.91 (2H, m), 8.40-8.43 (2H, m), 8.53 (1H, d), 8.71 (1H, d), 10.61 (1H,s), 13.60 (1H, s); IR (solid)3277, 3069, 2855, 2231, 1625; MS313.2(M+H)⁺.

EXAMPLE 332(5-Methyl-2H-pyrazol-3-yl)-(2-morpholin-4-yl-quinazolin-4-yl)-amine(III-104)

[0995] mp 223-224° C.; ¹H NMR (DMSO) δ 2.26(3H, s), 3.65(4H, m),3.75(4H, m), 6.44(1H, s), 7.12(1H, d), 7.33(1H, d), 7.56(1H, t),8.37(1H, d), 10.01(1H, s), 12.13(1H, br s); IR (solid) 1621, 1578, 1537,1475, 1434, 1385; MS 311.0 (M+H)⁺.

EXAMPLE 333(5-Methyl-2H-pyrazol-3-yl)-(2-piperazin-1-yl-quinazolin-4-yl)-amine(III-105)

[0996] mp 179-181° C.; ¹H NMR (DMSO) δ 2.26(3H, s), 2.74 (4H, br s),3.71(4H, br s), 6.43(1H, s), 7.08(1H, t), 7.30(1H, d), 7.53(1H, t),8.34(1H, d), 9.50(1H, s), 12.08(1H, br s); IR (solid) 2853, 1619, 1603,1566, 1549, 1539; MS 310.0 (M+H)⁺

EXAMPLE 334[2-(4-Methylpiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-106)

[0997] mp 148-150° C.; ¹H NMR (DMSO) δ 1.06(3H, d), 1.03(2H, m),1.51-1.70(3H, m), 2.26(3H, s), 2.86(2H, m), 4.73(2H, d), 6.44(1H, s),7.06(1H, d), 7.29(1H, d), 7.52(1H, t), 8.32(1H, d), 9.92(1H, s),12.09(1H, br s); IR (solid)2917, 2840, 1629, 1593, 1562, 1546, 1486; MS323.0 (M+H)⁺.

EXAMPLE 335[2-(4-Methylpiperazin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-107)

[0998] mp 105-107° C.; ¹H NMR (DMSO) δ 2.21(3H, s), 2.26(3H, s),2.34(4H, m), 3.75(4H, m), 6.45(1H, s), 7.09(1H, t), 7.31(1H, d),7.54(1H, t), 8.34(1H, d), 9.96(1H, s), 12.12(1H, br s); IR (solid) 2934,2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 (M+H)⁺.

EXAMPLE 336(5-Methyl-2H-pyrazol-3-yl)-(2-piperidin-1-yl-quinazolin-4-yl)-amine(III-108)

[0999] mp 294° C.; ¹H NMR (DMSO) δ 1.45-1.58 (4H, m), 1.63 (2H, m), 2.26(3H, s), 3.79 (4H, m), 6.45 (1H, br s), 7.06 (1H, t), 7.29 (1H, d), 7.52(1H, t), 8.33 (1H, d), 9.92 (1H, s), 12.11 (1H, br s); IR (solid) 2929,2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 (M+H)⁺.

EXAMPLE 337(2-Azepan-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-109)

[1000] mp 269° C.; ¹H NMR (DMSO) δ 1.50 (4H, br s), 1.76 (4H, br s),2.25 (3H, s), 3.78 (4H, t), 6.55 (1H, br s), 7.03 (1H, t), 7.28 (1H, d),7.50 (1H, t), 8.33 (1H, d), 9.92 (1H, s), 12.09 (1H, br s); IR (solid)3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486,1468, 1386, 1427; MS 323.3 (M+H)⁺.

EXAMPLE 338[2-(4-(2-Hydroxyethylpiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-110)

[1001] mp 175° C.; ¹H NMR (DMSO) δ 1.08 (2H, m), 1.38 (2H, m), 1.57-1.83(3H, m), 2.26 (3H, s), 2.85 (2H, t), 3.47 (2H, m), 4.38 (1H, t), 4.75(2H, d), 6.45 (1H, br s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.32(1H, d), 9.93 (1H, s), 12.12 (1H, br s); IR (solid) 3365, 3073, 2972,2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 (M+H)⁺.

EXAMPLE 339(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-guinazolin-4-yl]-amine(III-111)

[1002] To a solution of(5-cyclopropyl-1H-pyrazol-3-yl)-(2-chloro-quinazolin-4-yl)-amine (118mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine(0.49 mL, 4.1 mmol) and the reaction mixture heated at reflux overnight.The reaction mixture was concentrated in vacuo and the residue dissolvedin a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41mmol) was added and the mixture stirred at room temperature for 2 hours.The resulting suspension was filtered, washed with water (×2), andrinsed with Et₂O (×2) to afford III-111 as a white solid (123 mg, 85%):mp 190° C.; ¹H NMR (DMSO) δ 0.66 (2H, s), 0.93 (5H, br s), 1.07 (2H, d),1.66 (3H, s), 1.91 (1H, s), 2.85 (2H, t), 4.72 (2H, d), 6.33 (1H, s),7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.31 (1H, d), 9.95 (1H, s),12.18 (1H, br s); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494,1481, 1453, 1435, 1394; MS 349.2 (M+H)⁺.

EXAMPLE 340[2-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-112)

[1003] mp 191° C.; ¹H NMR (DMSO) δ 1.65 (4H, s), 2.26 (3H, s), 3.90 (4H,s), 3.93 (4H, s), 6.43 (1H, br s), 7.09 (1H, t), 7.32 (1H, d), 7.54 (1H,t), 8.35 (1H, d), 9.99 (1H, br s), 12.13 (1H, br s); IR (solid) 3069,2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS367.3 (M+H)⁺.

EXAMPLE 341[2-(4-Cyclopentylamino-piperidin-1-yl)-quinazolin-4-yl-(5-methyl-2H-pyrazol-3-yl)-amine(III-113)

[1004] mp 191° C.; ¹H NMR (DMSO) δ 1.33 (2H, d), 1.65 (4H, s), 1.87 (2H,d), 2.20 (1H, s), 2.26 (3H, s), 2.49 (2H, s), 3.00 (2H, t), 3.36 (2H,s), 4.61 (2H, d), 6.45 (1H, br s), 7.07 (1H, s), 7.31 (1H, d), 7.52 (1H,s), 8.33 (1H, d), 9.94 (1H, br s), 12.12 (1H, br s); IR (solid) 3371,2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 (M+H)⁺.

EXAMPLE 342[2-(4-Hydroxypiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-114)

[1005] mp 123° C.; ¹H NMR (DMSO) δ 1.34 (2H, d), 1.80 (2H, d), 2.26 (3H,s), 3.24 (2H, t), 3.72 (1H, br s), 4.39 (2H, d), 4.70 (1H, d), 6.44 (1H,br s), 7.07 (1H, t), 7.30 (1H, d), 7.53 (1H, t), 8.33 (1H, d), 9.94 (1H,br s), 12.11 (1H, br s); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600,1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 (M+H)⁺.

EXAMPLE 343(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-hydroxy-4-phenylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-115)

[1006] mp 131° C.; ¹H NMR (DMSO) δ 0.64 (2H, q), 0.93 (2H, q), 1.68 (2H,d), 1.83-1.97 (3H, m), 3.20-3.45 (2H, m), 4.69 (2H, d), 5.11 (1H, s),6.37 (1H, br s), 7.08 (1H, t), 7.20 (1H, t), 7.31 (3H, t), 7.49 (2H, d),7.53 (1H, t), 8.33 (1H, d), 9.98 (1H, br s), 12.18 (1H, br s); IR(solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559,1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427.6 (M+H)⁺.

EXAMPLE 344(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1,3-dihydro-isoindol-2-yl)-quinazolin-4-yl]-amine(III-116)

[1007] Prepared according to Method E-I to afford an off-white solid, mp237° C.; ¹H NMR (DMSO-d6) δ 0.79 (2H, s), 1.00 (2H, d), 1.99 (1H, m),4.92 (4H, d), 6.72 (1H, br s), 7.13 (1H, t), 7.33 (2H, s), 7.30-7.48(3H, m), 7.58 (1H, t), 8.40 (1H, d), 10.12 (1H, s), 12.17 (1H, s); IR(solid)3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391,1359, 1141, 1027, 877, 814; MS 369.4 (M+H)⁺.

EXAMPLE 345(2-Azepan-1-yl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(III-117)

[1008] mp 199-200° C.; ¹H NMR (DMSO-d6) δ 0.60-0.70 (2H, m), 0.90-1.00(2H, m), 1.45-1.57 (4H, m), 1.70-1.85 (4H, m), 1.88-1.97 (1H, m),3.75-3.87 (4H, m), 6.42 (1H, s), 7.02 (1H, t), 7.27 (1H, d), 7.49 (1H,t), 8.29 (1H, d), 9.91 (1H, s), 12.19 (1H, br s); IR (solid) 2929, 1624,1595, 1581, 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, 1000,825, 754; MS 349.2 (M+H)⁺.

EXAMPLE 346(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinazolin-4-yl]-amine(III-118): mp 182-184° C.; ¹H NMR (DMSO) δ 0.75 (2H, d), 1.02 (2H, d),1.96 (1H, m), 2.89 (2H, m), 4.05 (2H, m), 4.94 (2H, s), 6.46 (1H, s),7.10 (1H, t), 7.21 (4H, d), 7.37 (1H, d), 7.55 (1H, d), 8.36 (1H, d),10.05 (1H, s), 12.23 (1H, br s); IR (solid) 1621, 1581, 1560, 1537,1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 (M+H)⁺. EXAMPLE 347(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dihydro-indol-1-yl)-quinazolin-4-yl]-amine(III-119)

[1009] mp 150-153° C.; ¹H NMR (DMSO) δ 0.74 (2H, d), 0.98 (2H, d), 1.96(1H, m), 3.15 (2H, t), 4.25 (2H, t), 6.45 (1H, br s), 6.88 (1H, t), 7.09(1H, t), 7.20 (2H, m), 7.53 (1H, d), 7.65 (1H, t), 8.43 (2H, br s),10.09 (1H, s), 12.28 (1H, br s); IR (solid) 1621, 1588, 1577, 1564,1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 (M+H)⁺.

EXAMPLE 348(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-hydroxymethylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-120)

[1010] mp 142° C.; ¹H NMR (DMSO) δ 0.67 (2H, d), 0.96 (2H, d), 1.10 (2H,q), 1.55-1.70 (3H, m), 1.91 (1H, m), 2.85 (2H, t), 3.28 (2H, s), 4.48(1H, s), 4.76 (2H, d), 6.34 (1H, s), 7.06 (1H, t), 7.30 (1H, d), 7.52(1H, t), 8.31 (1H, d), 9.96 (1H, s), 12.19 (1H, s); IR (solid)3363,3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354,1314, 1241, 1186, 1091, 995, 941, 823; MS 365.8 (M+H)⁺.

EXAMPLE 349(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dihydro-2H-quinolin-1-yl)-quinazolin-4-yl]-amine(III-121)

[1011] mp 137-145° C.; ¹H NMR (DMSO-d6) δ 0.55 (2H, d), 0.88 (2H, d),1.78 (1H, m), 1.92 (2H, t), 2.75 (2H, t), 4.04 (2H, t), 6.20 (1H, br s),6.97 (1H, t), 7.14 (1H, m), 7.19 (1H, t), 7.42 (1H, d), 7.61 (1H, t),7.67 (1H, d), 8.43 (1H, d), 10.04 (1H, s), 12.21 (1H, br s); IR (solid)1622, 1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 (M+H)⁺.

EXAMPLE 350(5-Methoxycarbonyl-2H-pyrazol-3-yl)-[2-(piperidine-1-yl)-quinazolin-4-yl]-amine (III-122): ¹H NMR (500 MHz, CDCl₃) δ 1.7-1.8(6H,m), δ 3.8 (4H,m), δ 3.9 (3H, s), 6 5.5 (1H, s), δ 7.15 (1H, t), δ 7.4 (1H, d), δ 7.6(1H, t), δ 8.0 (1H, d). HPLC-Method B, (starting with 95% H₂O) R_(t) 7.4min; MS (ES+)353.24 (M+H). EXAMPLE 351[5-(Piperidine-1-carbonyl)-2H-pyrazol-3-yl]-[2-(piperidine-1-yl)-quinazolin-4-yl]-amine(III-123)

[1012] HPLC-Method B, (starting with 95% H₂O:0.1% TFA)R_(t) 8.0 min; MS(ES+)406.30, (ES−) 404.30.

EXAMPLE 352(5-Hydroxymethyl-2H-pyrazol-3-yl)-[2-(piperidin-1-yl)-quinazolin-4-yl]-amine(III-124)

[1013] To a solution of III-122 (10.0 mg, 0.028 mmol) in THF (6 mL) atambient temperature was slowly added a IM solution of LiA1H₄ in THF(0.05 mL, 0.05 mmol). After 15 minutes the solution was quenched withwater and 1N HCl. The product was extracted from the aqueous layer withEtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by preparatory HPLC toafford III-124 (4.0 mg, 44%). HPLC-Method B, (starting with 95% H₂O:0.1%TFA) R_(t) 6.1 min; MS (ES+)325.13 (M+H), (ES−)323.13 (M−H).

EXAMPLE 353(5-Carbamoyl-2H-pyrazol-3-yl)-[2-(piperidin-1-yl)-quinazolin-4-yl]-amine(III-125)

[1014] A solution of III-122 (1.5 g, 4.3 mmol) in 2.0 M NH₃/MeOH (100mL) was heated at 110° C. for 2 days. The dark brown reaction mixturewas concentrated in vacuo to afford a viscous oil which was purified bycolumn chromatography to yield 0.7 g (50%) of III-125. ¹H NMR (500 MHz,CD30D-d₃) δ 1.6 (4H, m), δ 1.7 (2H,m), δ 3.3 (1H, s), δ 3.8 (4H, m), δ5.5 (1H, s), δ 7.15 (1H, t), δ 7.45 (1H, d), δ 7.55 (1H, t), δ 8.0 (1H,d); HPLC-Method B, (starting with 95% H₂O:0.1% TFA)R_(t) 5.9 min; MS(ES+)338.13, (ES−)336.15.

EXAMPLE 354(5-Carbamoyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-126)

[1015] HPLC-Method B, (starting with 95% H₂0:0.1 TFA)R_(t) 6.4 min; MS(ES+)352.19, (ES−) 350.20.

EXAMPLE 355(5,7-Difluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-amine(III-127)

[1016]¹H NMR (500 MHz, DMSO-d6) δ 13.7 (s, 1H), 10.3 (s, br, 1H), 7.90(d, 2H), 7.52 (t, 1H), 7.45 (m, 3H), 7.26 (d, 1H), 2.99 (m, 2H), 2.75(m, 2H), 1.95 (br, 4H) ppm; MS (ES+)378.24 (M+H); (ES−)376.23 (M-H);HPLC-Method A, R_(t) 3.04 min.

EXAMPLE 356(2-Phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-trifluoromethyl-1H-indazol-3-yl)-amine(III-128)

[1017]¹H NMR (500 MHz, DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, br, 1H), 8.13(s, 1H), 7.86 (d, 2H), 7.78 (d, 1H), 7.69 (d, 1H), 7.50 (t, 1H), 7.35(dd, 2H), 2.89 (m, 2H), 2.72 (m, 2H), 1.90 (s, br, 4H) ppm; MS (ES+)410.24 (M+H); (ES−) 408.23 (M−H); HPLC-Method A, R_(t) 3.19 min.

EXAMPLE 357 (7-Fluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-129)

[1018]¹H NMR (500 MHz, DMSO-d6) δ 13.6 (s, 1H), 11.1 (s, br, 1H), 8.65(d, 1H), 8.03 (d, 2H), 7.95 (s, 2H), 7.67 (m, 1H), 7.45 (m, 2H), 7.33(t, 2H), 7.22 (dd, 1H), 6.99 (td, 1H) ppm. MS (ES+): m/e=356.20 (M+H);HPLC-Method A R_(t) 3.00 min.

EXAMPLE 358 (5-Fluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-130)

[1019]¹H NMR (500 MHz, DMSO-d6) δ 13.2 (s, 1H), 11.3 (s, br, 1H), 8.67(d, 1H), 8.04 (d, 2H), 7.96 (s, 2H), 7.70 (m, 1H), 7.58 (dd, 1H), 7.43(m, 4H), 7.28 (td, 1H) ppm. MS (ES+) 356.20 (M+H); HPLC-Method A, R_(t)3.00 min.

EXAMPLE 359(5,7-Difluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-131)

[1020]¹H NMR (500 MHz, DMSO-d6) δ 13.7 (s, 1H), 8.65 (d, 1H), 8.04 (d,2H), 7.95 (s, 2H), 7.68 (m, 1H), 7.45 (m, 1H), 7.35 (m, 4H) ppm. MS(ES+): m/e=374.17 (M+H); HPLC-Method A, R_(t) 3.07 min.

EXAMPLE 360(1H-Indazol-3-yl)-[2-(3-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(III-132)

[1021]¹H NMR (500 MHz, DMSO-d6) δ 7.06 (t, 1H), 7.42 (t, 1H), 7.59 (d,1H), 7.63 (t, 1H), 7.66 (d, 1H), 7.71 (m, 1H), 7.80 (d, 1H), 7.98 (m,2H), 8.33 (s, 1H), 8.46 (d, 1H), 8.71 (d, 1H), 11.04 (br. s, 1H), 12.97(s, 1H); EI−MS 406.1 (M+1); HPLC-Method A, R_(t) 3.15 min.

EXAMPLE 361(2-Phenyl-quinazolin-4-yl)-(1H-pyrazolo[4,3-b]pyridin-3-yl)-amine(III-133)

[1022]¹H NMR (500 MHz, DMSO-d6) δ 13.3 (s, br, 1H), 11.4 (s, br, 1H),8.78 (d, 1H), 8.58 (dd, 1H), 8.24 (d, 1H), 8.10 (m, 2H), 7.95 (d, 2H),7.86 (t, 1H), 7.56 (m, 2H), 7.44 (t, 2H) ppm. MS (ES+)339.11 (M+H);HPLC-Method A, R_(t) 2.63 min.

EXAMPLE 362[5-(3-Methoxy-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-134)

[1023]¹H NMR (500 MHz, MeOH-d4) δ 8.65 (d, 1H), 8.17 (m, 3H), 8.10 (d,1H), 7.90 (t, 1H), 7.75 (t, 1H), 7.58 (m, 2H), 7.25 (t, 1H), 6.95 (m,2H), 6.85 (d, 1H), 6.80 (s, 1H), 3.64 (s, 3H) ppm. MS (ES+):m/e=462.2(M+H).

EXAMPLE 363(6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-135)

[1024]¹H NMR (500 MHz, MeOH-d4) δ 8.61 (d, 1H), 8.13 (m, 3H), 8.05 (d,1H), 7.85 (t, 1H), 7.70 (t, 1H), 7.58 (m, 2H), 7.32 (m, 5H), 6.79 (s,1H) ppm. MS (ES+): m/e=432.2(M+H).

EXAMPLE 364[5-(4-Methoxy-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-136)

[1025] MS (ES+)462.2(M+H).

EXAMPLE 365[5-(2,4-Dichloro-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-137)

[1026]¹H NMR (500 MHz, MeOH-d4) δ 8.63 (d, 1H), 8.17 (m, 4H), 7.89 (t,1H), 7.73 (t, 1H), 7.61 (t, 2H), 7.57 (d, 1H), 7.32 (m, 1H), 7.21 (d,1H), 6.84 (s, 1H) ppm. MS (ES+): m/e=500.1(M+H).

EXAMPLE 366[6-Oxo-5-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-138)

[1027]¹H NMR (500 MHz, MeOH-d4) δ 8.55 (d, 1H), 8.19 (d, 2H), 7.92 (m,2H), 7.65 (m, 3H), 7.45 (t, 2H), 7.25 (t, 1H), 7.13 (t, 1H), 7.05 (t,1H), 6.75 (s, 1H) ppm. MS (ES+): m/e=500.2 (M+H).

EXAMPLE 367[6-Oxo-5-(4-Phenoxy-phenyl)-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-139)

[1028] MS (ES+) 524.3(M+H).

EXAMPLE 368[5-(4-Chloro-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-140)

[1029] MS (ES+)466.2(M+H).

EXAMPLE 369 (2-imidazol-1-yl-quinazolin-4-yl)-(1H-indazol-3-yl)-amine(III-141)

[1030]¹H NMR (500 MHz, DMSO-d6) δ 7.10 (t, 1H), 7.44 (t, 1H), 7.50 (br.s, 1H), 7.60 (d, 1H), 7.72 (m, 2H), 7.77 (m, 1H), 7.88 (d, 1H), 7.98 (t,1H), 8.73 (d, 1H), 8.96 (s, 1H), 11.23 (s, 1H), 13.06 (s, 1H); EI−MS328.1 (M+1); HPLC-Method A, R_(t) 2.93 min.

EXAMPLE 370

[1031](1H-Indazol-3-yl)-[2-(2-methyl-imidazol-1-yl-quinazolin-4-yl]-amine(III-142)

[1032]¹H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.10 (t, 1H), 7.43 (t,1H), 7.57 (d, 1H), 7.60 (d, 1H), 7.67 (d, 1H), 7.76 (td, 1H), 7.86 (d,1H), 7.91 (d, 1H), 8.01 (td, 1H), 8.72 (d, 1H), 11.15 (s, 1H), 13.10 (s,1H); EI−MS 342.1 (M+1); HPLC-Method A, R_(t) 3.06 min.

EXAMPLE 371 (1H-Indazol-3-yl)-(2-piperidin-1-yl-quinazolin-4-yl)-amine(III-143)

[1033]¹H NMR (500 MHz, DMSO-d6) δ 1.48 (m, 6H), 3.60 (m, 4H), 7.11 (t,1H), 7.52 (t, 1H), 7.55 (d, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.75 (d,1H), 7.90 (t, 1H), 8.58 (d, 1H), 11.82 (br. s, 1H), 13.25 (s, 1H); EI−MS345.1 (M+1); HPLC-Method A, R_(t) 3.03 min.

EXAMPLE 372(1H-Indazol-3-yl)-[2-(octahydro-quinolin-1-yl)-quinazolin-4-yl]-amine(III-144)

[1034]¹H NMR (500 MHz, DMSO-d6) δ 0.6-1.9 (m, 13H), 3.15 (m, 1H), 3.25(m, 1H), 4.0 (m, 1H), 7.10 (t, 0.5H), 7.12 (t, 0.5H), 7.55 (m, 2H), 7.66(d, 0.5 H), 7.69 (d, 0.5 H), 7.77 (d, 1H), 7.91 (t, 1H), 8.55 (d, 0.5H), 8.59 (d, 0.5 H), 11.46 (s, 0.5 H), 11.54 (s, 0.5 H), 11.78 (s, 0.5H), 11.84 (s, 0.5 H), 13.10 (s, 0.5 H), 13.12 (s, 0.5 H); EI−MS 399.3(M+1); HPLC-Method A, R_(t) 3.37 min.

EXAMPLE 373(1H-Indazol-3-yl)-[2-(2,6-dimethyl-morpholin-4-yl)-quinazolin-4-yl]-amine(III-145)

[1035]¹H NMR (500 MHz, DMSO-d6) δ 1.0 (m, 6H), 4.0 (m, 6H), 7.12 (t,1H), 7.41 (td, 1H), 7.56 (t, 1H), 7.58 (d, 1H), 7.68 (dd, 1H), 7.77 (t,1H), 7.93 (t, 1H), 8.60 (d, 1H), 11.69 (s, 1H), 13.16 (s, 1H); EI−MS375.3 (M+1); HPLC-Method A, R_(t) 2.93 min.

EXAMPLE 374 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrimidin-4-yl)-amine(IV-1)

[1036] mp 245-246° C.; ¹H NMR (DMSO) δ 2.26 (3H, s), 6.32 (1H, br s),7.07 (1H, br s), 7.48-7.54 (3H, m), 8.33-8.39 (3H, m), 9.87 (1H, s),12.03 (1H, s); IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393,1336; MS 252.2 (M+H)⁺.

EXAMPLE 375[6-(4-Acetamidophenylsulfanyl)-2-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-3)

[1037] A suspension of Fenclorim (4,6-dichloro-2-phenylpyrimidine)(0.1g, 0.44 mmol), 3-amino-5-methylpyrazole (0.045 g, 0.47 mmol), N,N-diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g,0.44 mmol) in n-butanol (5 ml) were heated at 117° C. for 18 hours. Thesolvent was removed in vacuo and the crude product purified by flashchromatography (silica gel, 3:2 Petrol:EtOAc) to afford 0.037 g (29%yield) of(6-Chloro-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as aoff-white solid. A suspension of the above pyrimidine (0.037 g, 0.13mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanolwas heated at 85° C. under nitrogen for 2 days. The reaction mixture wascooled to room temperature and the solvent removed in vacuo. Theconcentrate was dissolved in EtOAc, and washed with NaHCO₃ (sat, aq.).The organic layer is concentrated in vacuo, and the crude product bypreperative HPLC. The residual disulfide that still remained in themixture after HPLC may be removed by precipitation from EtOAc andfiltration. The mother liquor was concentrated to afford IV-3 (7 mg, 13%yield) as an off-white solid: mp 235-236° C.; ¹H NMR (DMSO) δ 2.10 (3H,s), 2.21 (3H, s), 6.33 (1H, br s), 7.50 (3H, m), 7.7-7.59 (2H, m),7.76-7.78 (2H, m), 8.25 (2H, m), 9.72, 10.26 and 11.93 (3 H, 3× br s);IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174,1102, 1089, 1027, 1015, 984; MS 417.3 (M+H)⁺.

EXAMPLE 376[2-(4-Methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-4)

[1038] mp 215-216° C.; ¹H NMR (CD₃OD) δ 0.96 (3H, d), 1.16 (2H, m), 1.66(3H, m), 2.27 (3H, s), 2.86 (2H, t), 4.58 (2H, m), 4.78 (2H,exch.protons), 6.13 (2H, m), 7.83 (1H, d); IR (solid) 1593, 1550, 1489,1436, 1331, 1246, 1231; MS 273.1 (M+H)⁺.

EXAMPLE 377[2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-5)

[1039] mp 185-187° C.; ¹H NMR (DMSO) δ 0.93 (3H, d), 1.06-1.18 (2H, m),1.68-1.80 (3H, m), 2.26 (3H, s), 3.01-3.12 (2H, m), 4.63 (1H, d), 4.80(1H, d), 6.39 (1H, s), 9.00 (1H, s), 10.41 (1H, s), 12.36 (1H, s); IR(solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2(M+H)⁺.

EXAMPLE 378[5-Amino-2-(4-Methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-6)

[1040] To a solution of IV-5 (48 mg, 0.151 mmol) in ethanol (2.0 mL) wasadded tin dichloride dihydrate (171 mg, 0.756 mmol) and the resultingmixture heated at reflux for 3 hours. The reaction was cooled to roomtemperature and poured onto a mixture of 1MNaOH:dichloromethane:propanol (18:8:4 mL) and stirred for 15 minutes.The layers were separated and the aqueous layer extracted twice withdichloromethane. The combined organic layers were concentrated in vacuoand the residue purified by flash chromatography (silica gel, gradientdichloromethane:MeOH) to afford IV-6 as a grey solid (27mg, 63%): ¹H NMR(DMSO) δ 0. 88-1.04 (5H, m), 1.55-1.62 (3H, m), 2.21 (3H, s), 2.70 (2H,m), 3.36 (2H, m), 4.40 (2H, m), 6.37 (1H, s), 7.49 (1H, s), 8.40 (1H,s), 11.92 (1H, br s); MS 288.2 (M+H)⁺.

EXAMPLE 379[5-Amino-6-methyl-2-(4-methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-7)

[1041] mp 172-175° C.; ¹H NMR (DMSO) δ 0.90 (3H, d), 1.03 (2H, m),1.52-1.62 (3H, m). 2.13 (3H, s), 2.20 (3H, s), 2.69 (2H, m), 3.92 (2H,br s), 4.44 (2H, d), 6.35 (1H, s), 8.41 (1H, s), 11.85 (1H, br s); IR(solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 (M+H)⁺.

EXAMPLE 380[6-Methyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IV-10)

[1042] MS 342.34 (M+H); HPLC-Method E, R_(t) 1.334 min.

EXAMPLE 381

[1043][2-(4-Chloro-phenyl)-6-methyl-pyrimidin-4-yl]-(5-furan-2-yl-2H-pyrazol-3-yl)-amine(IV-11)

[1044] MS 352.11 (M+H); HPLC Method E, R_(t) 1.194 min.

EXAMPLE 3825-Furan-2-yl-2H-pyrazol-3-yl)-(6-methyl-2-phenyl-pyrimidin-4-yl)-amine(IV-12)

[1045] MS 318.21 (M+H); HPLC-Method E, 1.192 min.

EXAMPLE 383(6-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-phenyl-2-yl-2H-pyrazol-3-yl)-amine(IV-13)

[1046] MS 396.24 (M+H); HPLC-Method E, R_(t) 1.419 min.

EXAMPLE 384(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(IV-14)

[1047] MS 386.08 (M+H); HPLC-Method E 1.347 min.

EXAMPLE 385[2-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-6-methyl-pyrimidin-4-yl-(5-furan-2-yl-2H-pyrazol-3-yl)-amine(IV-15)

[1048] MS 376.18 (M+H); HPLC-Method E, R_(t) 1.181 min.

EXAMPLE 386[2-(2,3-Dihydro-bezo[1,4]dioxin-2-yl)-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-16)

[1049] MS 338.17 (M+H); HPLC-Method E, R_(t) 1.082 min.

EXAMPLE 387(6-Ethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-17)

[1050] MS 280.18 (M+H); HPLC-Method E, R_(t) 1.024 min.

EXAMPLE 388 (6-Methyl-2-phenyl-pyrimidin-4-yl)-(5-phenyl-2H-pyrazol-3-yl)-amine (IV-19)

[1051] MS 328.51 (M+H); HPLC-Method E, R_(t) 1.192 min.

EXAMPLE 389[6-Ethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-20): MS 348.5 (M+H); HPLC-Method E, R_(t) 1.224 min. EXAMPLE 390(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-amine(IV-21)

[1052] MS 332.23 (M+H); HPLC-Method E, R_(t) 1.139 min.

EXAMPLE 391(6-Methoxymethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-22)

[1053] MS 296.31 (M+H); HPLC-Method E, R_(t) 0.971 min.

EXAMPLE 392(5,6-Dimethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-23)

[1054] MS 280.2 (M+H); HPLC-Method E, R_(t) 0.927 min.

EXAMPLE 393(6-Methyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-24)

[1055] MS 266.18 (M+H); HPLC-Method E, R_(t) 0.925 min.

Example 394[6-Ethyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-25)

[1056] MS 294.46 (M+H); HPLC-Method E, R_(t) 1.174 min.

EXAMPLE 395[2-(4-Chloro-phenyl)-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-26)

[1057] MS 314.42 (M+H); HPLC-Method E R_(t) 1.213 min.

EXAMPLE 396(5-Methyl-1H-pyrazol-3-yl)-(6-methyl-2-p-tolyl-pyrimidin-4-yl)-amine(IV-27)

[1058] MS 280.45 (M+H); HPLC-Method E, R_(t) 1.135 min.

EXAMPLE 397

[1059] (1H-Indazol-3-yl)-(6-methoxymethyl-2-phenyl-pyrimidin-4-yl)-amine(IV-28)

[1060]¹H NMR (500 MHz, DMSO) δ 3.57 (3H, s), 4.65 (2H, s), 7.23 (1H,J=7.5 Hz, t), 7.52 (1H, J=7.6 Hz, t), 7.63 (4H, m), 7.75 (1H, br), 8.13(1H, J=5.5 Hz, br d), 8.44 (1H, J=5.7 Hz, br d), 10.6 (1H, br), 12.8(1H, br s) ppm; HPLC-Method A, R_(t) 2.944 min; MS (FIA)332.1 (M+H)⁺.

EXAMPLE 398(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-thieno[3,2-dlpyrimidin-4-yl)-amine(IV-29)

[1061]¹H NMR (DMSO) δ 2.34 (3H, s), 6.66 (1H, s), 7.53 (1H, d), 7.84(1H, d), 8.32 (2H, d), 8.70 (2H, d); MS 309.6 (M+H)⁺.

EXAMPLE 399 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine (IV-30)

[1062] mp 225° C.; ¹H NMR (DMSO) δ 2.35 (3H, s), 6.81 (1H, s), 7.50-7.63(3H, m), 8.45-8.52 (2H, m), 8.54 (1H, d), 8.62 (1H, d), 9.20 (1H, s),10.79 (1H, s), 12.38 (1H, br s); IR (solid) 2958, 2917, 2852, 1593,1565, 1524, 1467, 1450; MS 303.2 (M+H)⁺.

EXAMPLE 400(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[2,3-d]pyrimidin-4-yl)-amine(IV-31)

[1063] To a solution of 4-chloro-2-phenyl-pyrido[2,3-d]pyrimidine (J.Pharm. Belg., 29, 1974, 145-148)(109 mg, 0.45 mmol) in THF (15 mL) wasadded 3-amino-5-methyl pyrazole (48 mg, 0.5 mmol) and the resultingmixture heated at 65° C. overnight. The mixture was cooled to roomtemperature and the resulting suspension was filtered and washed withEt₂O. The solid was dissolved in a mixture EtOH:water and the pHadjusted to pH 7. The aqueous was extracted twice with ethyl acetate andthe combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂, DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg,50%): mp 234° C.; ¹H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20-7.40(3H, m), 7.40-7.50 (3H, m), 8.60 (1H, d), 8.79 (1H, d), 12.82 (1H, brs); IR (solid)2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H)⁺.

EXAMPLE 401(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[3,4-dlpyrimidin-4-yl-)-amine(IV-32)

[1064] off-white solid, mp 232-233° C.; ¹H NMR (DMSO) δ 0.70-0.85 (2H,m), 0.90-1.05 (2H, m), 1.05-2.07 (1H, m), 6.75 (1H, s), 7.50-7.75 (3H,m), 8.40-8.70 (4H, m), 9.20 (1H, s), 10.80 (1H, s), 12.41 (1H); IR(solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781,667; MS 329.2 (M+H)⁺.

EXAMPLE 402[2-(4-Methylpiperidin-1-yl)-purin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-33)

[1065] To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) inanhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05g, 21.2 mmol). The resulting mixture was stirred at room temperature for48 h. The resulting precipitate was collected by filtration, washed withethanol, and dried under vacuum to afford 1.524 g (58% yield) of(2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used inthe next step without further purification. To a solution of(2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reactionmixture heated at reflux overnight. The solvent was evaporated and theresidue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassiumcarbonate (57 mg, 0.41 mmol) was added and the mixture was stirred atroom temperature for 2 hours. The resulting suspension was filtered,washed with water (×2) and rinsed with Et₂O (×2) to afford IV-33 as awhite solid (225 mg, 90%): mp >300° C.; ¹H NMR (DMSO) δ 0.91 (3H, d),1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m),6.40 (1H, s), 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR(solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3(M+H)⁺.

EXAMPLE 403(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-pyrrolo[3,2-d]pyrimidin-4-yl]-amine(IV-34)

[1066] white solid; ¹H NMR (DMSO) δ 0.65 (2H, m), 0.91-0.96 (5H, m),1.08 (2H, m), 1.58-1.64 (3H, m), 1.89 (1H, m), 2.77 (2H, t), 4.57 (2H,d), 6.09 (1H, s), 6.38 (1H, s), 7.33 (1H, s), 9.42 (1H, s), 10.65 (1H,s), 12.02 (1H, br s); MS 338.3 (M+H)⁺.

EXAMPLE 404[6-Benzyl-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(IV-35)

[1067]¹H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H), 10.4 (s, br, 1H), 9.73(s, 1H, TFA-OH), 8.00 (d, 2H), 7.64 (m, 2H), 7.59 (dd, 1H), 7.52 (m,3H), 7.41 (t, 1H), 7.31 (m, 3H), 7.14 (dd, 1H), 4.58 (s, 2H), 4.35 (br,2H), 3.74 (m, 2H), 3.17 (s, 2H) ppm. MS (ES+): m/e=451.30 (M+H);HPLC-Method A, T_(ret) 2.96 min.

EXAMPLE 405(5-Fluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-amine(IV-36)

[1068] Prepared from IV-35 (0.13 mmol) by treatment with an equal weightof Pd/C (10%) in 4.4% HCOOH in MeOH at room temperature for 12 h. Themixture was filtered through celite, the filtrate was evaporated, andcrude product was purified by HPLC to afford IV-36 as yellow solid in35% yield. ¹H NMR (500 MHz, DMSO-d6) δ 12.9 (s, 1H), 9.06 (s, 1H), 7.99(d, 2H), 7.57 (dd, 1H), 7.34 (m, 1H), 7.28 (m, 3H), 7.22 (d, 1H), 3.83(s, 2H), 3.05 (m, 2H), 2.72 (m, 2H) ppm. MS (ES+): m/e=361.20 (M+H);HPLC-Method A, T_(ret) 2.68 min.

EXAMPLE 406 (5-Methyl-2H-pyrazol-3-yl)-(3-phenyl-isoquinolin-1-yl)-amine(V-1)

[1069] To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem.,20, 1983, 121-128)(0.33 g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added3-amino-5-methylpyrazole (0.27g, 2.74 mmol) and potassium carbonate(0.57g, 4.13 mmol) and the resulting mixture was heated at reflux for 6hours. The reaction mixture was then cooled and solvent removed invacuo. The residue was extracted twice with ethyl acetate and thecombined organic layers washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, gradient DCM-MeOH) to afford V-1 as a colourlessoil; ¹H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H, m), 7.52(2H,m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m), 8.29(1H, s),8.54 (1H, d); MS 301.2 (M+H)⁺.

EXAMPLE 407(1H-Indazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinoline-1-yl]-amine(V-2)

[1070] A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline(100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) inethanol (3 mL) was heated at 160 C. and the solvent evaporated with astream of nitrogen. The remaining oil was then heated at 160 C. for 18hours under nitrogen. The resulting melt was dissolved in 5%methanol:dichloromethane (50 mL), washed with saturated aqueous sodiumbicarbonate (1×25 mL) then dried over magnesium sulfate. Purification bysilica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2as a yellow solid (35 mg, 27%). ¹H NMR (500 MHz, d₆-DMSO) δ 9.78 (br s,1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.70-7.68 (m,1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.38(m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95-6.92 (m, 1H), 5.76 (s,1H); LC−MS (ES+) m/e=405.18 (M+H); HPLC-Method D R_(t) 2.74 min.

EXAMPLE 408(5,7-Difluoro-1H-indazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine(V-3)

[1071] Prepared from 5,7-difluoro-1H-indazol-3-ylamineto afford compoundV-3 as a yellow solid (90 mg, 63%). ¹H NMR (500 MHz, d₆-DMSO) δ 13.25(s, 1H), 9.92 (br s, 1H), 8.61 (d, 1H), 7.9 (d, 1H), 7.81-7.49 (m, 6H),7.26-7.2 (m, 2H), 7.12-7.10 (m, 1H); LC−MS (ES+) m/e=441.16 (M+H);HPLC-Method D, R_(t) 3.58 min.

EXAMPLE 409 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine(V-4)

[1072] To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20,1983, 121-128)(0.53 g, 2.21 mmol) in diphenylether (5 mL) was added3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixtureheated at 200° C. overnight with stirring. The reaction mixture wascooled to ambient temperature then petroleum ether (20 mL) was added andthe resulting precipitate was isolated by filtration. The crude solidwas purified by flash chromatography (SiO₂, gradient DCM-MeOH) to affordV-4 as a white solid: mp 242-244° C.; ¹H NMR (DMSO) δ 2.27(3H, s),6.02(1H, s), 7.47(2H, d), 7.53-7.40(2H, br m), 7.67(1H, m), 7.92(1H, m),8.09(2H, d), 8.48(2H, m), 9.20(1H, s), 12.17(1H, br s); IR (solid) 1584,1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)⁺.

EXAMPLE 410 (1H-Indazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine (V-5)

[1073]¹H NMR (500 MHz, d₆-DMSO) δ 12.78 (s, 1H), 9.50 (s, 1H), 8.65 (d,1H), 8.15 (s, 1H), 8.04-7.98 (m, 3H), 7.94 (s, 1H), 7.78-7.75 (m, 1H),7.60-7.40 (m, 6H), 7.15-7.10 (m, 1H). LC−MS (ES+) m/e=337.11 (M+H);HPLC-Method D, R_(t) 2.10 min.

EXAMPLE 411(2-Phenyl-quinolin-4-yl)-(1H-pyrazolo[4,3-b]pyridin-3-yl)-amine (V-6)

[1074]¹H NMR (500 MHz, DMSO-d6) δ 13.6 (s, 1H), 11.4 (s, 1H), 8.94 (d,1H), 8.61 (dd, 1H), 8.23 (d, 1H), 8.16 (dd, 1H), 8.12 (t, 1H), 7.89 (t,1H), 7.86 (d, 1H), 7.65 (m, 4H), 7.54 (s, 1H), 7.52 (dd, 1H) ppm. MS(ES+): m/e=338.11 (M+H); HPLC-Method A, HPLC-Method D, R_(t) 2.91 min.

EXAMPLE 412(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl] -amine(V-7)

[1075]¹H NMR (500 MHz, d₆-DMSO) δ 12.68 (s, 1H), 9.51 (s, 1H), 8.7 (d,1H), 7.95-7.89 (m, 2H), 7.83-7.70 (m, 3H), 7.68-7.62 (m, 2H), 7.60 (s,1H), 7.55-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.12-7.09(m, 1H); LC−MS (ES+) m/e=405.15 (M+H); HPLC-Method D R_(t) 2.25 min.

EXAMPLE 413(5,7-Difluoro-[1-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(V-8)

[1076]¹H NMR (500 MHz, d₆-DMSO)8 13.31 (s, 1H), 9.49 (s, 1H), 8.70-8.67(m, 1H), 7.96-7.92 (m, 1H), 7.85-7.66 (m, 7H), 7.63-7.60 (m, 1H),7.42-7.40 (m, 1H). LC−MS (ES+) m/e=441.18 (M+H); HPLC-Method D R_(t)2.39 min.

EXAMPLE 414[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-(1H-pyrazolo[4,3-blpyridin-3-yl)-amine(V-9)

[1077]¹H NMR (500 MHz, DMSO-d6) δ 13.6 (s, 1H), 11.6 (s, br, 1H), 8.98(d, 1H), 8.57 (dd, 1H), 8.12 (m, 3H), 7.97 (m, 2H), 7.86 (m, 3H), 7.49(dd, 1H), 7.23 (s, 1H) ppm. MS (ES+): m/e=406.20 (M+H); HPLC-Method AR_(t) 2.91 min.

EXAMPLE 415 (2-Phenyl-quinazolin-4-yl)-(2H-[1,2,4]triazol-3-yl)-amine(IX-154)

[1078] off-white solid, mp 266-267° C.; ¹H NMR (DMSO) δ 7.50-7.70 (4H,m), 7.85-8.00 (2H, m), 8.15-8.25 (2H, m), 8.37-8.45 (2H, m), 8.58 (1H,d), 13.90 (1H, br s); IR (solid)3344, 3059, 1630, 1609, 1570, 1557,1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760,676, 667, 654; MS 289.2 (M+H)⁺.

EXAMPLE 416(5-Methyl-2H-[1,2,4]triazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(IX-155)

[1079]¹H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.42 (d, J=6.7 Hz, 2H),7.79 (m, 4H), 8.03 (m, 2H), 7.74 (m, 4H), 2.51 (s, 3H) ppm. MS (ES+):m/e=303.08 (M+H); HPLC-Method A, R_(t) 2.64 min.

EXAMPLE 417(2H-[1,2,3,4-Triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-y]-amine(IX-47)

[1080] Pale yellow solid (52% yield). ¹H NMR (500 MHz, DMSO-d6) 88.54(s, 1H), 8.15 (s, br, 1H), 7.91 (t, 1H), 7.85 (m, 2H), 7.76 (m, 3H),7.66 (t, 1H) ppm. MS (ES+): m/e=357.13 (M+H); (ES−): m/e=355.15 (M−H);HPLC-Method A, R_(t) 2.81 min.

EXAMPLE 418(5-Methyl-2H-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(IX-38)

[1081] Pale yellow solid (54% yield). ¹H NMR (500 MHz, DMSO-d6) δ 8.44(s, br, 1H), 7.92 (m, 3H), 7.84 (m, 1H), 7.77 (m, 2H), 7.68 (t, 1H),2.28 (s, 3H) ppm. MS (ES+): m/e=371.14 (M+H); (ES−): m/e=369.18 (M−H);HPLC-Method A, R_(t) 2.89 min.

EXAMPLE 419(5-Methylsulfanyl-2-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(IX-156)

[1082] Pale yellow solid (65% yield). ¹H NMR (500 MHz, DMSO-d6) δ 8.56(br, 1H), 7.90 (t, 1H), 7.84 (m, 2H), 7.78 (m, 2H), 7.67 (m, 2H), 2.51(s, 3H, buried by DMSO) ppm. MS (ES+): m/e=403.12 (M+H); (ES−):m/e=401.16 (M−H); HPLC-Method A, R_(t) 3.20 min.

EXAMPLE 420(1H-[1,2,4]Triazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine(IX-175)

[1083] A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline(0.326 mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3mL) was heated at 160° C. and the solvent evaporated with a stream ofnitrogen. The remaining oil was then heated at 160° C. for 18 hoursunder nitrogen. The resulting melt was dissolved in 5%methanol/dichloromethane (50 mL), washed with saturated aqueous sodiumbicarbonate (1×25 mL) then dried over magnesium sulfate. Purification bysilica gel chromatography afforded IX-175 as a colorless oil (4% yield).¹H NMR (500 MHz, CDCl₃) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H),7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m,1H). LC−MS (ES+)356.16 (M+H); HPLC-Method D, R_(t) 3.55 min.

EXAMPLE 421 (2-Phenyl-quinolin-4-yl)-(1H-[1,2,4]triazol-3-yl)-amine(IX-176)

[1084] Pale yellow solid (30% yield). ¹H NMR (500 MHz, d₆-DMSO) δ 13.82(s, 1H), 9.91 (s, 1H), 8.80 (s, 1H), 8.70-8.65 (m, 1H), 8.55 (s, 1H),8.15-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.75-7.72 (m, 1H), 7.57-7.49 (m,3H). LC−MS (ES+) m/e=288.11 (M+H); HPLC-Method D, R_(t) 1.55 min.

EXAMPLE 422(1H-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(IX-177)

[1085] Pale yellow solid (46% yield). ¹H NMR (500 MHz, d₆-DMSO) δ 13.70(s, 1H), 9.98 (s, 1H), 8.70 (d, 1H), 8.49 (s, 1H), 8.30 (s, 1H),7.94-7.88 (m, 2H), 7.80-7.68 (m, 3H), 7.64-7.56 (m, 2H). LC−MS (ES+)m/e=356.18 (M+H); HPLC-Method D, R_(t) 1.68 min.

EXAMPLE 423(1-H-Indazol-3-yl)-[5-methyl-6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-251)

[1086] Colorless film; 2% yield; ¹H-NMR (500 MHz, CD₃OD) δ 7.84 (m, 2H),7.71 (m, 3H), 7.41 (t, 2H), 7.14 (m, 1H), 3.74 (m, 4H), 3.69 (m, 4H),1.24 (s, 3H) ppm; HPLC-Method A R_(t) 3.26 min; MS (FIA)455.1 (M+H).

BIOLOGICAL TESTING

[1087] The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

BIOLOGICAL TESTING EXAMPLE 1

[1088] K_(i) DETERMINATION FOR THE INHIBITION OF GSK-3

[1089] Compounds were screened for their ability to inhibit GSK-3β (AA1-420) activity using a standard coupled enzyme system (Fox et al.(1998) Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, MO) and 300 μM peptide(HSSPHQS(PO₃H₂) EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[1090] An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The K_(i) values were determined from the ratedata as a function of inhibitor concentration.

[1091] The following compounds were shown to have K_(i) values less than0.1 μM for GSK-3: compounds II-1, II-105, II-33, II-34, II-36, II-39,II-38, II-39, II-40, II-41, II-42, II-46, II-57, II-59, II-60, II-61,II-62, II-63, II-64, II-66, II-67, II-69, II-70, II-53, II-71, II-99,II-73, II-74, II-75, II-76, II-77, II-7, II-8, II-9, II-10, II-24,II-19, II-78, II-54, 11-79, II-80, II-81, II-82, II-83, II-84, II-56,II-86, II-20, II-25, II-26, II-85, II-21, II-27, II-28, II-87, II-88,II-29, II-11, II-12, II-30, II-31, II-13, II-14, II-15, II-16, II-17,II-18, II-79, II-23, II-2, II-90, II-91, II-92, II-93, II-3, II-4, II-S,II-6, II-94, II-95, II-96, II-107, II-108, II-109, II-110, II-124,II-125, II-111, II-112, II-113, II-114, II-115, II-116, II-117, II-118,II-119, II-120, II-121, II-208, III-8, III-7, III-9, III-37, III-38,III-39, III-40, III-42, III-45, III-46, III-47, III-48, III-49, III-51,III-52, III-53, III-54, III-55, III-56, III-57, III-58, III-59, III-60,III-61, III-62, III-63, III-30, III-65, III-66, III-67, III-70, III-73,III-31, III-75, III-76, III-77, III-33, III-34, III-106, III-108,III-109, III-111, III-35, III-116, III-117, III-118, III-119, III-120,III-121, III-127, III-128, III-141, III-130, III-131, IV-15, IV-16,IV-17, IV-20, IV-25, IV-26, IV-30, IV-34, V-3, and IX-47.

[1092] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for GSK-3: compounds II-103, II-104, II-35, II-44, II-45,II-49, II-50, II-97, II-101, II-22, II-32, III-41, III-43, III-44,III-28, III-50, III-29, III-64, III-71, III-74, III-78, III-82, III-88,III-90, III-102, III-105, III-107, III-110, III-112, III-114, III-115,III-122, III-124, III-124, IV-1, III-1, III-138, III-140, III-142,III-129, III-132, III-134, III-135, III-136, IV-1, IV-10, IV-1l, IV-12,IV-13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV-6, IV-7,IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V-7, IX-38, IX-154, andIX-177.

[1093] The following compounds were shown to have K_(i) values between1.0 and 20 μM for GSK-3: compounds II-43, II-65, II-48, II-47, II-51,II-68, II-52, II-72, II-100, II-98, II-89, III-68, III-81, III-83,III-91, III-94, III-95, III-96, III-97, III-98, III-99, III-100,III-101, III-103, III-123, III-137, III-139, III-143, III-145, III-146,V-4, V-8, IX-156, and IX-176.

BIOLOGICAL TESTING EXAMPLE 2 K_(I) DETERMINATION FOR THE INHIBITION OFAURORA-2

[1094] Compounds were screened in the following manner for their abilityto inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al(1998) Protein Sci 7, 2249).

[1095] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration.

[1096] The following compounds were shown to have K_(i) values less than0.1 μM for Aurora-2: compounds II-33, II-34, II-36, II-37, II-40, II-41,II-55, III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42,III-44, III-45, III-46, III-47, III-48, III-49, III-50, III-51, III-52,III-53, III-54, III-55, III-56, III-57, III-59, III-60, III-61, III-63,III-30, III-65, III-66, III-67, III-70, III-31, III-76, III-77, III-78,III-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110,III-111, III-112, III-114, III-35, III-115, III-116, III-117, III-118,III-119, III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

[1097] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for Aurora-2: compounds II-1, II-105, II-35, II-38,II-39, II-42, II-64, II-70, II-53, II-99, II-77, II-79, II-86, II-20,II-93, II-94, III-28, III-58, III-64, III-71, III-73, III-74, III-75,III-102, III-105, III-107, III-113, III-124, III-1, III-130, IV-1, IV-3,IV-4, IV-6, IV-29, IV-33, and V-4.

[1098] The following compounds were shown to have K_(i) values between1.0 and 20 μM for Aurora-2: compounds II-103, II-104, II-57, II-59,II-61, II-63, II-67, II-69, II-75, II-76, II-10, II-19, II-78, II-54,II-80, II-82, II-21, II-90, 11-91, II-96, II-107, III-68, III-79,III-82, III-101, III-103, III-127, III-141, III-129, III-132, IV-31,V-2, IX-47, IX-154, and IX-177.

BIOLOGICAL TESTING EXAMPLE 3 CDK-2 INHIBITION ASSAY

[1099] Compounds were screened in the following manner for their abilityto inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

[1100] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP,and 100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale,Calif.) was added a DMSO solution of a compound of the present inventionto a final concentration of 30 μM. The resulting mixture was incubatedat 30° C. for 10 min.

[1101] The reaction was initiated by the addition of 10 μL ofCDK-2/Cyclin A stock solution to give a final concentration of 25 nM inthe assay. The rates of reaction were obtained by monitoring absorbanceat 340 nm over a 5-minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The Ki values were determined from therate data as a function of inhibitor concentration.

BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY

[1102] Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%) for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl_(2,) 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

[1103] The following compounds were shown to have a Ki value of <1 μMfor ERK-2: III-109, III-111, III-115, III-117, III-118, III-120, andIV-4.

[1104] The following compounds were shown to have a K_(i) value ofbetween 1 μM and 12 μM for ERK-2: III-63, III-40, and III-108.

BIOLOGICAL TESTING EXAMPLE 5 AKT INHIBITION ASSAY

[1105] Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998)7, 2249).Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2,25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrate concentrations inthe assay were 170 μM ATP (Sigma Chemicals) and 200 μM peptide (RPRAATF,American Peptide, Sunnyvale, Calif.). Assays were carried out at 30° C.and 45 nM AKT. Final concentrations of the components of the coupledenzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/MLpyruvate kinase and 10 μg/ml lactate dehydrogenase.

[1106] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY

[1107] The compounds were evaluated as inhibitors of human Src kinaseusing either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-Based Assay

[1108] The compounds were assayed as inhibitors of full lengthrecombinant human Src kinase (from Upstate Biotechnology, cat. no.14-117) expressed and purified from baculo viral cells. Src kinaseactivity was monitored by following the incorporation of ³³p from ATPinto the tyrosine of a random poly Glu-Tyr polymer substrate ofcomposition, Glu:Tyr =4:1 (Sigma, cat. no. P-0275). The following werethe final concentrations of the assay components: 0.05 M HEPES, pH 7.6,10 MM MgCl₂, 2 mM DTT, 0.25 mg/ml BSA, 10 μM ATP (1-2 μCi ³³P-ATP perreaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Srckinase. In a typical assay, all the reaction components with theexception of ATP were pre-mixed and aliquoted into assay plate wells.Inhibitors dissolved in DMSO were added to the wells to give a finalDMSO concentration of 2.5%. The assay plate was incubated at 30° C. for10 min before initiating the reaction with ³³P-ATP. After 20 min ofreaction, the reactions were quenched with 150 μl of 10% trichloroaceticacid (TCA) containing 20 mM Na₃PO₄. The quenched samples were thentransferred to a 96-well filter plate (Whatman, UNI-Filter GF/F GlassFiber Filter, cat no. 7700-3310) installed on a filter plate vacuummanifold. Filter plates were washed four times with 10% TCA containing20 mM Na₃PO₄ and then 4 times with methanol. 200 μl of scintillationfluid was then added to each well. The plates were sealed and the amountof radioactivity associated with the filters was quantified on aTopCount scintillation counter. The radioactivity incorporated wasplotted as a function of the inhibitor concentration. The data wasfitted to a competitive inhibition kinetics model to get the K_(i) forthe compound.

Src Inhibition Assay B: Spectrophotometric Assay

[1109] The ADP produced from ATP by the human recombinant Srckinase-catalyzed phosphorylation of poly Glu-Tyr substrate wasquanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci7, 2249). In this assay one molecule of NADH is oxidised to NAD forevery molecule of ADP produced in the kinase reaction. The disappearanceof NADH can be conveniently followed at 340 nm.

[1110] The following were the final concentrations of the assaycomponents: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/mlpoly Glu-Tyr, and 25 nM of recombinant human Src kinase. Finalconcentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 200 μM NADH, 30 μg/ml pyruvate kinase and 10μg/ml lactate dehydrogenase.

[1111] In a typical assay, all the reaction components with theexception of ATP were pre-mixed and aliquoted into assay plate wells.Inhibitors dissolved in DMSO wereadded to the wells to give a final DMSOconcentration of 2.5%. The assay plate was incubated at 30° C. for 10min before initiating the reaction with 100 μM ATP. The absorbancechange at 340 nm with time, the rate of the reaction, was monitored on amolecular devices plate reader. The data of rate as a function of theinhibitor concentration was fitted to compettive inhibition kineticsmodel to get the Ki for the compound.

[1112] The following compounds were shown to have a K_(i) value of <100nM on SRC: III-31, III-32, III-33, III-34, III-35, III-47, III-65,III-66, III-37, III-38, III-39, III-40, III-42, III-44, III-48, III-49,III-70, III-45, III-78, III-76, and IV-32.

[1113] The following compounds were shown to have a K_(i) value ofbetween 100 nM and 1 μM for SRC: III-63, III-71, III-75, III-73, III-72,III-74, III-80, III-50, IV-30.

[1114] The following compounds were shown to have a K_(i) value ofbetween 1 μM and 6 μM for SRC: III-79, IV-1, and IV-31.

[1115] While we have hereinbefore presented a number of embodiments ofthis invention, it is apparent that our basic construction can bealtered to provide other embodiments which utilize the compounds andmethods of this invention. Therefore, it will be appreciated that thescope of this invention is to be defined by the appended claims ratherthan by the specific embodiments which have been represented by way ofexample.

We claim:
 1. A compound of formula IV:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is independentlysubstituted at any substitutable ring carbon by oxo or —R⁵, and at anysubstitutable ring nitrogen by —R⁴, provided that when Ring D is asix-membered aryl or heteroaryl ring, —R⁵ is hydrogen at each orthocarbon position of Ring D; R^(x) and R^(y) are independently selectedfrom T—R³, or R^(x) and R^(y) are taken together with their interveningatoms to form a fused, unsaturated or partially unsaturated, 5-8membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur,or nitrogen, wherein any substitutable carbon on said fused ring isoptionally and independently substituted by T—R³, and any substitutablenitrogen on said ring is substituted by R⁴; T is a valence bond or aC₁₋₄ alkylidene chain; R² and R^(2′) are independently selected from —R,—T—W—R⁶, or R² and R^(2′) are taken together with their interveningatoms to form a fused, 5-8 membered, unsaturated or partiallyunsaturated, ring containing 0-3 ring heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein said fused ring is optionallysubstituted by up to three groups independently selected from halo, oxo,—CN, —NO₂, —R⁷, or —V—R⁶; R³ is selected from —R, -halo, ═O, —OR,—C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N (R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms; each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴on the same nitrogen are taken together to form a 5-8 memberedheterocyclyl or heteroaryl ring; each R⁵ is independently selected from—R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N (R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C (R⁶)₂N (R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is—C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C (R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R ⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—; each R⁶ is independently selected from hydrogen or anoptionally substituted C₁₋₄ aliphatic group, or two R⁶ groups on thesame nitrogen atom are taken together with the nitrogen atom to form a5-6 membered heterocyclyl or heteroaryl ring; and each R⁷ iSindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group, or two R⁷ on the same nitrogen are taken together withthe nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl. 2.The compound according to claim 1, wherein said compound has one or morefeatures selected from the group consisting of: (a) Ring D is anoptionally substituted ring selected from a phenyl, pyridinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl ring; (b) R^(x) is hydrogen or C₁₋₄ aliphaticand R^(y) is T—R³, or R^(x) and R^(y) are taken together with theirintervening atoms to form an optionally substituted 5-7 memberedunsaturated or partially unsaturated ring having 1-2 ring heteroatoms;and (c) R^(2′) is hydrogen or methyl and R² is T—W—R⁶ or R, wherein W is—C (R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, or —CON (R⁶)—, and R is an optionally substitutedgroup selected from C₁₋₆ aliphatic or phenyl, or R² and R^(2′) are takentogether with their intervening atoms to form a substituted orunsubstituted benzo, pyrido, pyrimido, or partially unsaturated6-membered carbocyclo ring.
 3. The compound according to claim 2,wherein: (a) Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b)R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 1-2 ring heteroatoms; and (c) R^(2′) is hydrogen or methyland R² is T—W—R⁶ or R, wherein W is —C(R⁶)₂O—, —C (R⁶)₂N(R⁶)—, —CO—,—CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, or —CON (R⁶)—,and R is an optionally substituted group selected from C₁₋₆ aliphatic orphenyl, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido, orpartially unsaturated 6-membered carbocyclo ring.
 4. The compoundaccording to claim 2, wherein said compound has one or more featuresselected from the group consisting of: (a) Ring D is an optionallysubstituted ring selected from phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b)R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, or R^(x)and R^(y) are taken together with their intervening atoms to form a 5-7membered unsaturated or partially unsaturated ring having 1-2 ringnitrogens, wherein said ring is optionally substituted with —R, halo,oxo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;and (c) each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —So₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.
 5. The compoundaccording to claim 4, wherein: (a) Ring D is an optionally substitutedring selected from phenyl, pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b)R^(x)is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, or R^(x) andR^(y) are taken together with their intervening atoms to form a 5-7membered unsaturated or partially unsaturated ring having 1-2 ringnitrogens, wherein said ring is optionally substituted with —R, halo,oxo, —OR, —C(═O)R, —CO2R, —COCOR, —NO₂, —CN, —S(O)R, —SO2R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;and (c) each R⁵ is independently selected from halo, oxo, CN, NO₂,—N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR,—C(O)R, or a substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.
 6. The compoundaccording to claim 4, wherein said compound has one or more featuresselected from the group consisting of: (a) R^(x) and R^(y) are takentogether with their intervening atoms to form a 6-membered unsaturatedor partially unsaturated ring having 1-2 ring nitrogens, optionallysubstituted with halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- or dialkylamino, mono- ordialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 memberedheteroaryl; (b) each R⁵ is independently selected from -halo, —CN, -oxo,—SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstituted groupselected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, and C₁₋₆ aliphatic;and (c) R^(2′) is hydrogen and R² is T—W—R⁶ or R, wherein W is—C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —C—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, or—CON(R⁶)—, and R is an optionally substituted group selected from C₁₋₆aliphatic or phenyl, or R² and R^(2′) are taken together with theirintervening atoms to form a substituted or unsubstituted benzo, pyrido,or partially unsaturated 6-membered carbocyclo ring optionallysubstituted with -halo, oxo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl,—NO₂, —O(C₁₋₄ alkyl), —CO2(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group.
 7. The compound according to claim 6, wherein: (a)R^(x) and R^(y) are taken together with their intervening atoms to forma 6-membered unsaturated or partially unsaturated ring having 1-2 ringnitrogens, optionally substituted with halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆alkoxy, (C₁₋₆ alkyl) carbonyl, (C₁₋₆ alkyl) sulfonyl, mono- ordialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl; (b) each R⁵ isindependently selected from -halo, —CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R,or a substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, and C₁₋₆ aliphatic; and (c) R^(2′) is hydrogenand R² is T—W—R⁶ or R, wherein W is —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—,—CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, or —CON(R⁶)—, and R is anoptionally substituted group selected from C₁₋₆ aliphatic or phenyl, orR² and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, or partially unsaturated6-membered carbocyclo ring optionally substituted with -halo, oxo,—N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl),—NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄alkyl) is a straight, branched, or cyclic alkyl group.
 8. The compoundaccording to claim 7, wherein said compound is selected from Table
 3. 9.A composition comprising a compound according to any of claims 1-8 and apharmaceutically acceptable carrier.
 10. The composition according toclaim 9 further comprising a second therapeutic agent.
 11. A method ofinhibiting GSK-3 or Aurora activity in a patient comprising the step ofadministering to a patient a therapeutically effective amount of thecomposition according to claim
 9. 12. The method according to claim 11,wherein said method inhibits GSK-3 activity in a patient.
 13. A methodof inhibiting GSK-3 or Aurora activity in a biological sample comprisingcontacting said biological sample with the compound according toclaim
 1. 14. A method of treating a disease that is alleviated bytreatment with an GSK-3 inhibitor, said method comprising the step ofadministering to a patient in need of such a treatment a therapeuticallyeffective amount of the composition according to claim
 9. 15. The methodaccording to claim 14 further comprising the step of administering to apatient a second therapeutic agent.
 16. The method according to claim14, wherein said disease is diabetes.
 17. The method according to claim14, wherein said disease is Alzheimer's disease.
 18. The methodaccording to claim 14, wherein said disease is schizophrenia.
 19. Amethod of enhancing glycogen synthesis in a patient in need thereof,which method comprises the step of administering to a patient atherapeutically effective amount of the composition according to claim9.
 20. A method of lowering blood levels of glucose in a patient in needthereof, which method comprises the step of administering to a patient atherapeutically effective amount of the composition according to claim9.
 21. A method of inhibiting the production of hyperphosphorylated Tauprotein in a patient in need thereof, which method comprises the step ofadministering to a patient a therapeutically effective amount of thecomposition according to claim
 9. 22. A method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, which methodcomprises the step of administering to a patient a therapeuticallyeffective amount of the composition according to claim
 9. 23. A methodof treating a disease that is alleviated by treatment with an aurorainhibitor, which method comprises the step of administering to a patientin need of such a treatment a therapeutically effective amount of thecomposition according to claim
 9. 24. The method according to claim 23,further comprising the step of administering to a patient a secondtherapeutic agent.
 25. The method according to claim 23 wherein saiddisease is cancer.